DNA replication licensing factor MCM8 is a protein that in humans is encoded by the MCM8gene.[1][2]
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.[2]
MCM8-deficient mice are defective in gametogenesis and display genome instability due to impaired homologous recombination.[3] 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.[3] 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.[4] 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.[4]
File:Homologous Recombination.jpgA 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.[5] 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.[5]
↑ 3.03.1Lutzmann 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. PMID22771120.
Ota T, Suzuki Y, Nishikawa T, et al. (2004). "Complete sequencing and characterization of 21,243 full-length human cDNAs". Nat. Genet. 36 (1): 40–5. doi:10.1038/ng1285. PMID14702039.
Deloukas P, Matthews LH, Ashurst J, et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature. 414 (6866): 865–71. doi:10.1038/414865a. PMID11780052.
Bonaldo MF, Lennon G, Soares MB (1997). "Normalization and subtraction: two approaches to facilitate gene discovery". Genome Res. 6 (9): 791–806. doi:10.1101/gr.6.9.791. PMID8889548.
