DMC1 (gene)

Last updated
DMC1
Protein DMC1 PDB 1v5w.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases DMC1 , DMC1H, LIM15, dJ199H16.1, DNA meiotic recombinase 1
External IDs OMIM: 602721 MGI: 105393 HomoloGene: 5135 GeneCards: DMC1
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_001278208
NM_007068
NM_001363017

NM_001278226
NM_010059

RefSeq (protein)

NP_001265137
NP_008999
NP_001349946

NP_001265155
NP_034189

Location (UCSC) Chr 22: 38.52 – 38.57 Mb Chr 15: 79.45 – 79.49 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Meiotic recombination protein DMC1/LIM15 homolog is a protein that in humans is encoded by the DMC1 gene. [5] [6] [7] [8]

Contents

Meiotic recombination protein Dmc1 is a homolog of the bacterial strand exchange protein RecA. Dmc1 plays the central role in homologous recombination in meiosis by assembling at the sites of programmed DNA double strand breaks and carrying out a search for allelic DNA sequences located on homologous chromatids. The name "Dmc" stands for "disrupted meiotic cDNA" and refers to the method used for its discovery which involved using clones from a meiosis-specific cDNA library to direct knock-out mutations of abundantly expressed meiotic genes

The Dmc1 protein is one of two homologs of RecA found in eukaryotic cells, the other being Rad51. DMC1 and RAD51 share over 50% amino acid similarity. [9] In budding yeast, Rad51 serves as a strand exchange protein in mitosis where it is critical for the repair of DNA breaks. Rad51 is converted to an accessory factor for Dmc1 during meiosis by inhibition of its strand exchange activity. [10] Homologs of DMC1 are well conserved and have been identified in many organisms including divergent fungi, plants and mammals including humans. [5] [6] [7] [8]

Discovery

The DMC1 gene and protein were discovered in the budding yeast S. cerevisiae by Douglas Bishop in 1992 when he was a postdoctoral fellow in the laboratory of Nancy Kleckner at Harvard University. [11]

Structure

Human DMC1 is a homomultimer in the form of an octameric ring with a diameter of 140 Å and a hole in the middle of 45 Å. [12] [9] DMC1 binds preferentially to ssDNA over dsDNA. [12] Unlike RecA and Rad51, DMC1 does not appear to form a helical filament on DNA, instead forming rings with DNA passing through the center. [12] hDMC1 can conduct D-loop formation in supercoiled DNA. [13] DMC1 has weak ATPase activity and is able to promote heteroduplex formation in the presence of a non-hydrolysable analog of ATP, indicating a requirement for ATP binding over ATP hydrolysis. [14] DMC1 also shows enhanced binding to nucleosomes with histone tails removed, indicating that chromosome architecture may play a role in DMC1 binding, but not Rad51. [15]

Function

The protein encoded by this gene is essential for meiotic homologous recombination. Genetic recombination in meiosis plays an important role in generating diversity of genetic information and facilitates the reductional segregation of chromosomes that must occur for formation of gametes during sexual reproduction.

During meiosis, programmed DNA double strand breaks (DSBs) are introduced by topoisomerase-like enzyme Spo11. DSBs are lengthened through the actions of exonucleases to trim the 5' ends and form long 3' single-stranded DNA (ssDNA) overhangs. These 3' overhangs are stabilized by the effects of single strand binding proteins (SSBs) to protect the ssDNA and prevent the formation of secondary structures. DMC1 is loaded onto the 3' ssDNA to form a right-handed helical nucleoprotein filament. Subsequently, this nucleoprotein filament conducts a homology search in a homologous DNA region. Single-strand invasion in a complementary region in the homologous chromosome by the 3'-ended DNA strand forms a heteroduplex in the form of a displacement loop (D-loop). This D-Loop is extended as DNA repair synthesis occurs, forming a Holliday junction. Resolution of this Holiday junction results in crossover or non-crossover product. [16] Crossover products are generated to a lesser extent than non-crossover products. [17]

Like other members of the Rad51/RecA family, Dmc1 stabilizes strand exchange intermediates (Rad1/RecA-stretched DNA, or RS-DNA) in stretched triplets similar to B form DNA. Each molecule of the protein binds a triplet of nucleotides, and the strength of that binding, as assessed by the change in Gibbs free energy, can be assessed by the length of time that a labelled dsDNA probe with a short homologous sequence remains bound to a DNA containing a short region of homology to it. A study of this type has shown that a mismatch in any of the three positions at the end of a stretch of homology will not increase the length of time that the probe remains bound, and in Rad51 or RecA constructs an internal mismatch will cause a similar reduction in binding time. All of the enzymes are capable of "stepping over" a mismatch and continuing to bind the probe more firmly if a longer region of homology exists. However, with Dmc1 a triplet with a single internal (but not terminal) mismatch will contribute to the stability of probe binding to a similar extent as one without a mismatch. In this way, Dmc1 is specially suited to its role as a meiosis-specific recombinase, as this activity permits it more effectively to catalyze recombination between sequences that are not perfectly matched. [18]

Interactions

DMC1 (gene) has been shown to interact with RAD51 and the Structural Maintenance of Chromosome 5/6 (SMC5/6) complex. [19] [14] The protein has also been shown to bind Tid1(Rdh54), Mei5/Sae3, and Hop2/Mnd1. All of these interacting proteins act to enhance Dmc1's activity in purified systems and are also implicated as being required for Dmc1 function in cells.

DMC1 has also been shown to interact with FIGNL1. FIGNL1 is believed to promote the disassembly of DMC1 during male meiosis. [20]

Rad51

During meiosis, the two recombinases, Rad51 and Dmc1, interact with single-stranded DNA to form specialized filaments that are adapted for facilitating recombination between homologous chromosomes. Both Dmc1 and Rad51 have an intrinsic ability to self-aggregate. [21] The presence of Rad51 filaments stabilizes adjacent Dmc1 filaments and conversely Dmc1 stabilizes adjacent Rad51 filaments. A model was proposed in which Dmc1 and Rad51 form separate filaments on the same single stranded DNA and cross-talk between the two recombinases affects their biochemical properties. [21]

During meiosis, even in the absence of Rad51 strand exchange activity, Dmc1 appears to be able to repair all meiotic DNA breaks, and this absence does not affect meiotic crossing over rates. [22]

Hop2/Mnd1

Hop2 and Mnd1 associate into a heterodimer which itself has affinity for dsDNA, and to a lesser extent, ssDNA. Hop2/Mnd1 stimulates strand-exchange activity of DMC1 in vitro. The interaction of Hop2/Mnd1 and DMC1 are thought to promote preferential binding of DMC1 to ssDNA and bring homologs into close proximity. [23] [24]

SCM5/6

DMC1 interacts with the Structural Maintenance of Chromosomes 5/6 (SMC5/6) complex. SCM5/6 complex inhibits the formation of DNA intermediates and is involved in their resolution. There is evidence that SCM5/6 interacts with and inhibit meiotic localization of DMC1. Rad51 can inhibit this interaction, and this may be its role as an accessory factor during meiotic homologous recombination. [19]

Clinical significance

Mutations in the DMC1 gene are associated with male infertility, due to nonobstructive azoospermia, where the testes produce little to no sperm. [25] In mice, a single amino acid change can prevent crossing over and lead to meiotic arrest through an autosomal dominant mechanism. [26]

Related Research Articles

<i>Entamoeba</i> Genus of internal parasites

Entamoeba is a genus of Amoebozoa found as internal parasites or commensals of animals. In 1875, Fedor Lösch described the first proven case of amoebic dysentery in St. Petersburg, Russia. He referred to the amoeba he observed microscopically as Amoeba coli; however, it is not clear whether he was using this as a descriptive term or intended it as a formal taxonomic name. The genus Entamoeba was defined by Casagrandi and Barbagallo for the species Entamoeba coli, which is known to be a commensal organism. Lösch's organism was renamed Entamoeba histolytica by Fritz Schaudinn in 1903; he later died, in 1906, from a self-inflicted infection when studying this amoeba. For a time during the first half of the 20th century the entire genus Entamoeba was transferred to Endamoeba, a genus of amoebas infecting invertebrates about which little is known. This move was reversed by the International Commission on Zoological Nomenclature in the late 1950s, and Entamoeba has stayed 'stable' ever since.

<span class="mw-page-title-main">Meiosis</span> Cell division producing haploid gametes

Meiosis is a special type of cell division of germ cells and apicomplexans in sexually-reproducing organisms that produces the gametes, such as sperm or egg cells. It involves two rounds of division that ultimately result in four cells with only one copy of each chromosome (haploid). Additionally, prior to the division, genetic material from the paternal and maternal copies of each chromosome is crossed over, creating new combinations of code on each chromosome. Later on, during fertilisation, the haploid cells produced by meiosis from a male and a female will fuse to create a cell with two copies of each chromosome again, the zygote.

<span class="mw-page-title-main">Chromosomal crossover</span> Cellular process

Chromosomal crossover, or crossing over, is the exchange of genetic material during sexual reproduction between two homologous chromosomes' non-sister chromatids that results in recombinant chromosomes. It is one of the final phases of genetic recombination, which occurs in the pachytene stage of prophase I of meiosis during a process called synapsis. Synapsis begins before the synaptonemal complex develops and is not completed until near the end of prophase I. Crossover usually occurs when matching regions on matching chromosomes break and then reconnect to the other chromosome.

<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

Genetic recombination is the exchange of genetic material between different organisms which leads to production of offspring with combinations of traits that differ from those found in either parent. In eukaryotes, genetic recombination during meiosis can lead to a novel set of genetic information that can be further passed on from parents to offspring. Most recombination occurs naturally and can be classified into two types: (1) interchromosomal recombination, occurring through independent assortment of alleles whose loci are on different but homologous chromosomes ; & (2) intrachromosomal recombination, occurring through crossing over.

<span class="mw-page-title-main">Homologous chromosome</span> Chromosomes that pair in fertilization

A couple of homologous chromosomes, or homologs, are a set of one maternal and one paternal chromosome that pair up with each other inside a cell during fertilization. Homologs have the same genes in the same loci, where they provide points along each chromosome that enable a pair of chromosomes to align correctly with each other before separating during meiosis. This is the basis for Mendelian inheritance, which characterizes inheritance patterns of genetic material from an organism to its offspring parent developmental cell at the given time and area.

RecQ helicase is a family of helicase enzymes initially found in Escherichia coli that has been shown to be important in genome maintenance. They function through catalyzing the reaction ATP + H2O → ADP + P and thus driving the unwinding of paired DNA and translocating in the 3' to 5' direction. These enzymes can also drive the reaction NTP + H2O → NDP + P to drive the unwinding of either DNA or RNA.

<span class="mw-page-title-main">RecA</span> DNA repair protein

RecA is a 38 kilodalton protein essential for the repair and maintenance of DNA. A RecA structural and functional homolog has been found in every species in which one has been seriously sought and serves as an archetype for this class of homologous DNA repair proteins. The homologous protein is called RAD51 in eukaryotes and RadA in archaea.

<span class="mw-page-title-main">Homologous recombination</span> Genetic recombination between identical or highly similar strands of genetic material

Homologous recombination is a type of genetic recombination in which genetic information is exchanged between two similar or identical molecules of double-stranded or single-stranded nucleic acids.

Recombinases are genetic recombination enzymes.

<span class="mw-page-title-main">RAD51</span>

DNA repair protein RAD51 homolog 1 is a protein encoded by the gene RAD51. The enzyme encoded by this gene is a member of the RAD51 protein family which assists in repair of DNA double strand breaks. RAD51 family members are homologous to the bacterial RecA, Archaeal RadA and yeast Rad51. The protein is highly conserved in most eukaryotes, from yeast to humans.

<span class="mw-page-title-main">Bloom syndrome protein</span> Mammalian protein found in humans

Bloom syndrome protein is a protein that in humans is encoded by the BLM gene and is not expressed in Bloom syndrome.

<span class="mw-page-title-main">RAD52</span> Protein-coding gene in the species Homo sapiens

RAD52 homolog , also known as RAD52, is a protein which in humans is encoded by the RAD52 gene.

<span class="mw-page-title-main">DNA repair and recombination protein RAD54-like</span> Protein-coding gene in the species Homo sapiens

DNA repair and recombination protein RAD54-like is a protein that in humans is encoded by the RAD54L gene.

In molecular biology, a displacement loop or D-loop is a DNA structure where the two strands of a double-stranded DNA molecule are separated for a stretch and held apart by a third strand of DNA. An R-loop is similar to a D-loop, but in this case the third strand is RNA rather than DNA. The third strand has a base sequence which is complementary to one of the main strands and pairs with it, thus displacing the other complementary main strand in the region. Within that region the structure is thus a form of triple-stranded DNA. A diagram in the paper introducing the term illustrated the D-loop with a shape resembling a capital "D", where the displaced strand formed the loop of the "D".

<span class="mw-page-title-main">MSH4</span> Protein-coding gene in the species Homo sapiens

MutS protein homolog 4 is a protein that in humans is encoded by the MSH4 gene.

<span class="mw-page-title-main">RAD54B</span> Protein-coding gene in the species Homo sapiens

DNA repair and recombination protein RAD54B is a protein that in humans is encoded by the RAD54B gene.

<span class="mw-page-title-main">MCM8</span> Protein-coding gene in the species Homo sapiens

DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

<span class="mw-page-title-main">Synthesis-dependent strand annealing</span>

Synthesis-dependent strand annealing (SDSA) is a major mechanism of homology-directed repair of DNA double-strand breaks (DSBs). Although many of the features of SDSA were first suggested in 1976, the double-Holliday junction model proposed in 1983 was favored by many researchers. In 1994, studies of double-strand gap repair in Drosophila were found to be incompatible with the double-Holliday junction model, leading researchers to propose a model they called synthesis-dependent strand annealing. Subsequent studies of meiotic recombination in S. cerevisiae found that non-crossover products appear earlier than double-Holliday junctions or crossover products, challenging the previous notion that both crossover and non-crossover products are produced by double-Holliday junctions and leading the authors to propose that non-crossover products are generated through SDSA.

GT198 is a human oncogene located within the BRCA1 locus at chromosome 17q21. It encodes protein product named GT198, Hop2 or TBPIP. The GT198 gene is found to be mutated with its protein overexpressed in human cancers including breast and ovarian cancers.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000100206 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022429 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 Habu T, Taki T, West A, Nishimune Y, Morita T (February 1996). "The mouse and human homologs of DMC1, the yeast meiosis-specific homologous recombination gene, have a common unique form of exon-skipped transcript in meiosis". Nucleic Acids Research. 24 (3): 470–477. doi:10.1093/nar/24.3.470. PMC   145652 . PMID   8602360.
  6. 1 2 Sato S, Seki N, Hotta Y, Tabata S (August 1995). "Expression profiles of a human gene identified as a structural homologue of meiosis-specific recA-like genes". DNA Research. 2 (4): 183–186. doi: 10.1093/dnares/2.4.183 . PMID   8590282.
  7. 1 2 Thorslund T, Esashi F, West SC (June 2007). "Interactions between human BRCA2 protein and the meiosis-specific recombinase DMC1". The EMBO Journal. 26 (12): 2915–2922. doi:10.1038/sj.emboj.7601739. PMC   1894777 . PMID   17541404.
  8. 1 2 "Entrez Gene: DMC1 DMC1 dosage suppressor of mck1 homolog, meiosis-specific homologous recombination (yeast)".
  9. 1 2 Passy SI, Yu X, Li Z, Radding CM, Masson JY, West SC, Egelman EH (September 1999). "Human Dmc1 protein binds DNA as an octameric ring". Proceedings of the National Academy of Sciences of the United States of America. 96 (19): 10684–10688. Bibcode:1999PNAS...9610684P. doi: 10.1073/pnas.96.19.10684 . PMC   17943 . PMID   10485886.
  10. Cloud V, Chan YL, Grubb J, Budke B, Bishop DK (September 2012). "Rad51 is an accessory factor for Dmc1-mediated joint molecule formation during meiosis". Science. 337 (6099): 1222–1225. Bibcode:2012Sci...337.1222C. doi:10.1126/science.1219379. PMC   4056682 . PMID   22955832.
  11. Bishop DK, Park D, Xu L, Kleckner N (May 1992). "DMC1: a meiosis-specific yeast homolog of E. coli recA required for recombination, synaptonemal complex formation, and cell cycle progression". Cell. 69 (3): 439–456. doi:10.1016/0092-8674(92)90446-j. PMID   1581960. S2CID   45890186.
  12. 1 2 3 Masson JY, West SC (February 2001). "The Rad51 and Dmc1 recombinases: a non-identical twin relationship". Trends in Biochemical Sciences. 26 (2): 131–136. doi:10.1016/S0968-0004(00)01742-4. PMID   11166572.
  13. Li Z, Golub EI, Gupta R, Radding CM (October 1997). "Recombination activities of HsDmc1 protein, the meiotic human homolog of RecA protein". Proceedings of the National Academy of Sciences of the United States of America. 94 (21): 11221–11226. Bibcode:1997PNAS...9411221L. doi: 10.1073/pnas.94.21.11221 . PMC   23422 . PMID   9326590.
  14. 1 2 Masson JY, Davies AA, Hajibagheri N, Van Dyck E, Benson FE, Stasiak AZ, et al. (November 1999). "The meiosis-specific recombinase hDmc1 forms ring structures and interacts with hRad51". The EMBO Journal. 18 (22): 6552–6560. doi:10.1093/emboj/18.22.6552. PMC   1171718 . PMID   10562567.
  15. Kobayashi W, Takaku M, Machida S, Tachiwana H, Maehara K, Ohkawa Y, Kurumizaka H (April 2016). "Chromatin architecture may dictate the target site for DMC1, but not for RAD51, during homologous pairing". Scientific Reports. 6: 24228. Bibcode:2016NatSR...624228K. doi:10.1038/srep24228. PMC   4823753 . PMID   27052786.
  16. Da Ines O, Bazile J, Gallego ME, White CI (August 2022). "DMC1 attenuates RAD51-mediated recombination in Arabidopsis". PLOS Genetics. 18 (8): e1010322. doi: 10.1371/journal.pgen.1010322 . PMC   9451096 . PMID   36007010.
  17. Hunter N (October 2015). "Meiotic Recombination: The Essence of Heredity". Cold Spring Harbor Perspectives in Biology. 7 (12): a016618. doi:10.1101/cshperspect.a016618. PMC   4665078 . PMID   26511629.
  18. Lee JY, Terakawa T, Qi Z, Steinfeld JB, Redding S, Kwon Y, et al. (August 2015). "DNA RECOMBINATION. Base triplet stepping by the Rad51/RecA family of recombinases". Science. 349 (6251): 977–981. doi:10.1126/science.aab2666. PMC   4580133 . PMID   26315438.
  19. 1 2 Chen H, He C, Wang C, Wang X, Ruan F, Yan J, et al. (August 2021). "RAD51 supports DMC1 by inhibiting the SMC5/6 complex during meiosis". The Plant Cell. 33 (8): 2869–2882. doi:10.1093/plcell/koab136. PMC   8408460 . PMID   34009315.
  20. Ito M, Furukohri A, Matsuzaki K, Fujita Y, Toyoda A, Shinohara A (October 2023). "FIGNL1 AAA+ ATPase remodels RAD51 and DMC1 filaments in pre-meiotic DNA replication and meiotic recombination". Nature Communications. 14 (1): 6857. Bibcode:2023NatCo..14.6857I. doi:10.1038/s41467-023-42576-w. PMC   10611733 . PMID   37891173.
  21. 1 2 Crickard JB, Kaniecki K, Kwon Y, Sung P, Greene EC (March 2018). "Spontaneous self-segregation of Rad51 and Dmc1 DNA recombinases within mixed recombinase filaments". The Journal of Biological Chemistry. 293 (11): 4191–4200. doi: 10.1074/jbc.RA117.001143 . PMC   5858004 . PMID   29382724.
  22. Singh G, Da Ines O, Gallego ME, White CI (2017). "Analysis of the impact of the absence of RAD51 strand exchange activity in Arabidopsis meiosis". PLOS ONE. 12 (8): e0183006. Bibcode:2017PLoSO..1283006S. doi: 10.1371/journal.pone.0183006 . PMC   5552350 . PMID   28797117.
  23. Bugreev DV, Huang F, Mazina OM, Pezza RJ, Voloshin ON, Camerini-Otero RD, Mazin AV (June 2014). "HOP2-MND1 modulates RAD51 binding to nucleotides and DNA". Nature Communications. 5 (1): 4198. Bibcode:2014NatCo...5.4198B. doi:10.1038/ncomms5198. PMC   4279451 . PMID   24943459.
  24. Chen YK, Leng CH, Olivares H, Lee MH, Chang YC, Kung WM, et al. (July 2004). "Heterodimeric complexes of Hop2 and Mnd1 function with Dmc1 to promote meiotic homolog juxtaposition and strand assimilation". Proceedings of the National Academy of Sciences of the United States of America. 101 (29): 10572–10577. Bibcode:2004PNAS..10110572C. doi: 10.1073/pnas.0404195101 . PMC   490024 . PMID   15249670.
  25. "DMC1 DNA meiotic recombinase 1 [Homo sapiens (human)] - Gene". National Center for Biotechnology Information (NCBI). U.S. National Library of Medicine. Retrieved 2023-12-05.
  26. Bannister LA, Pezza RJ, Donaldson JR, de Rooij DG, Schimenti KJ, Camerini-Otero RD, Schimenti JC (May 2007). "A dominant, recombination-defective allele of Dmc1 causing male-specific sterility". PLOS Biology. 5 (5): e105. doi: 10.1371/journal.pbio.0050105 . PMC   1847842 . PMID   17425408.

Further reading