MCM8

MCM8
Identifiers
Aliases MCM8, C20orf154, dJ967N21.5, POF10, minichromosome maintenance 8 homologous recombination repair factor
External IDs MGI: 1913884 HomoloGene: 12001 GeneCards: MCM8
Genetically Related Diseases
gestational hypertension, human immunodeficiency virus infectious disease[1]
Orthologs
Species Human Mouse
Entrez

84515

66634

Ensembl

ENSG00000125885

ENSMUSG00000027353

UniProt

Q9UJA3

Q9CWV1

RefSeq (mRNA)

NM_001281520
NM_001281521
NM_001281522
NM_032485
NM_182802

NM_001291054
NM_025676

RefSeq (protein)

NP_001268449.1
NP_001268450.1
NP_001268451.1
NP_115874.3
NP_877954.1

NP_001277983.1
NP_079952.2

Location (UCSC) Chr 20: 5.95 – 6 Mb Chr 2: 132.82 – 132.84 Mb
PubMed search [2] [3]
Wikidata
View/Edit HumanView/Edit Mouse

DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8 gene.[4][5]

The protein encoded by this gene is one of the highly conserved mini-chromosome maintenance proteins (MCM) that are essential for the initiation of eukaryotic genome replication. The hexameric protein complex formed by the MCM proteins is a key component of the pre-replication complex (pre_RC) and may be involved in the formation of replication forks and in the recruitment of other DNA replication related proteins. This protein contains the central domain that is conserved among the MCM proteins. This protein has been shown to co-immunoprecipitate with MCM4, 6 and 7, which suggests that it may interact with other MCM proteins and play a role in DNA replication. Alternatively spliced transcript variants encoding distinct isoforms have been described.[5]

DNA repair

MCM8-deficient mice are defective in gametogenesis and display genome instability due to impaired homologous recombination.[6] Male MCM8 (-/-) mice are sterile because spermatocytes are blocked in meiotic prophase I. Female MCM8(-/-) mice have arrested primary follicles and frequently develop ovarian tumors.[6] MCM8 protein forms a complex with MCM9.

In the plant Arabidopsis thaliana, MCM8 is required for a pathway of meiotic DNA double-strand break repair.[7] It was proposed that MCM8 is involved with RAD51 in a backup pathway that repairs meiotic double-strand breaks without yielding crossovers when the major recombination pathway, which relies on DMC1, fails.[7]

A current model of meiotic recombination, initiated by a double-strand break or gap, followed by pairing with an homologous chromosome and strand invasion to initiate the recombinational repair process. Repair of the gap can lead to crossover (CO) or non-crossover (NCO) of the flanking regions. CO recombination is thought to occur by the Double Holliday Junction (DHJ) model, illustrated on the right, above. NCO recombinants are thought to occur primarily by the Synthesis Dependent Strand Annealing (SDSA) model, illustrated on the left, above. Most recombination events appear to be the SDSA type.

MCM8 forms a complex with MCM9 that is required for DNA resection by the MRN complex (MRE11-RAD50-NBS1) at double strand breaks to generate single-stranded DNA ends.[8] The formation of single-strand ends is an early step in homologous recombination (see Figure). MCM8/MCM9 interacts with MRN and is required for the nuclease action and stable association of MRN with double-strand breaks.[8]

In humans, an MCM8 mutation can give rise to premature ovarian failure, as well as chromosomal instability.[9]

See also

References

  1. ↑ "Diseases that are genetically associated with MCM8 view/edit references on wikidata".
  2. ↑ "Human PubMed Reference:".
  3. ↑ "Mouse PubMed Reference:".
  4. ↑ Gozuacik D, Chami M, Lagorce D, Faivre J, Murakami Y, Poch O, Biermann E, Knippers R, Brechot C, Paterlini-Brechot P (Jan 2003). "Identification and functional characterization of a new member of the human Mcm protein family: hMcm8". Nucleic Acids Res. 31 (2): 570–9. doi:10.1093/nar/gkg136. PMC 140502Freely accessible. PMID 12527764.
  5. 1 2 "Entrez Gene: MCM8 MCM8 minichromosome maintenance deficient 8 (S. cerevisiae)".
  6. 1 2 Lutzmann M, Grey C, Traver S, Ganier O, Maya-Mendoza A, Ranisavljevic N, Bernex F, Nishiyama A, Montel N, Gavois E, Forichon L, de Massy B, Méchali M (2012). "MCM8- and MCM9-deficient mice reveal gametogenesis defects and genome instability due to impaired homologous recombination". Mol. Cell. 47 (4): 523–34. doi:10.1016/j.molcel.2012.05.048. PMID 22771120.
  7. 1 2 Crismani W, Portemer V, Froger N, Chelysheva L, Horlow C, Vrielynck N, Mercier R (2013). "MCM8 is required for a pathway of meiotic double-strand break repair independent of DMC1 in Arabidopsis thaliana". PLoS Genet. 9 (1): e1003165. doi:10.1371/journal.pgen.1003165. PMC 3536722Freely accessible. PMID 23300481.
  8. 1 2 Lee KY, Im JS, Shibata E, Park J, Handa N, Kowalczykowski SC, Dutta A (2015). "MCM8-9 complex promotes resection of double-strand break ends by MRE11-RAD50-NBS1 complex". Nat Commun. 6: 7744. doi:10.1038/ncomms8744. PMC 4525285Freely accessible. PMID 26215093.
  9. ↑ AlAsiri S, Basit S, Wood-Trageser MA, Yatsenko SA, Jeffries EP, Surti U, Ketterer DM, Afzal S, Ramzan K, Faiyaz-Ul Haque M, Jiang H, Trakselis MA, Rajkovic A (2015). "Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability". J. Clin. Invest. 125 (1): 258–62. doi:10.1172/JCI78473. PMC 4382257Freely accessible. PMID 25437880.

Further reading


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