A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress

“…[14], documented a homozygous mutation carriers of MCM9 presented Colorectal carcinoma along with POI. Nevertheless, the3 mutation carriers of Guo etal's cohort did not have any history of tumors.So the emphasis on why long term follow up is so significant regarding watching for tumors ,in particular the hormone sensitive tumors needs to be emphasized to the patients with MCM9 mutations.This might be in view of its role in DNA replication-correlated healing by sustenance of fork integrity at the time of replication stress [15].…”

Section: Discussionmentioning

confidence: 99%

An update on the Genetics of Premature ovarian insufficiency (POI) with special emphasis on mini chromosome maintenance (MCM)8 &9-A Short Communication

Kaur¹

2023

ESD

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Objective- Premature ovarian insufficiency (POI) comprises of enhanced gonadotropins, specifically follicle stimulating hormone (FSH) and irregularity/ lack of menstruation inwomen< 40yrs of age.Having reviewed literatureearlier with a case report on genetics of POI with the advent of whole exon sequencing,here we aimed to update the same. Methods-Relevant search engineswas done to update literature on genetics in POI emphasizing on the part of maintenance complex competence 8/9 (MCM8 and MCM9) in POIon what had not been covered earliertill date. Results-On search it was evident that all the patients that manifested biallelic variations carrier of MCM9 presented with primary amenorrhea whereas the heterozygous carriers possessed greater probability of secondary amenorrhea. Further homozygous variations of MCM8,BRCA1 andRAD54L, were observed combined with MCM9 variations that coexisted in patients with MCM9 variations that coexisted in patients that pointed towards an accrual of action of genetic abnormalities impacted the robustness of POI. Furthermore, female mice with absence of Mcm8 or Mcm9 presented with infertility, which correlated with early germ cells elimination possessing a susceptibility for cancers,inclusive of Hepatocellular carcinoma (HCC)and ovarian tumors or hyperplasia. Recently in a Chinese cohort of 192POIwomen(192controls) 3 innovative heterozygous mutations were observed. Functional evaluation on HEK293 Kidney cells transfected with mutant plasmids illustrated that cells overexpressing mutant MCM9 possessed dysfunctional DNA repair ability besides haploinsufficiency of MCM9 was posited. Conclusions-With homozygous mutation carriers of MCM9 presenting CRC, HCC emphasis is laid on long term follow up significance for tumor watching possibly by DNA replication correlated healing by sustenance of fork integrity at the time ofreplication stress.

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“…Instead, the recruitment of RAD51 on the forks was suggested to be mediated by the direct interaction with DNA polymerase alpha [ 61 ], RAD54 [ 57 ], or RAD51C [ 62 , 63 ]. Additionally, MCM8 and MCM9, which are implicated in the pre-replication complex (pre-RC) formation, DNA replication elongation and aid in the normal progression of the replication fork, favor the recruitment of BRCA1 and RAD51 when the fork stalling occurs, to protect them from excessive degradation [ 64 ]. One hypothesis is that the ssDNA tracts are relatively short, thus no mediator (such as BRCA2) is required to remove RPA from them.…”

Section: Noncatalytic Roles Of Rad51 In Dna Replicationmentioning

confidence: 99%

Noncanonical Roles of RAD51

Thomas

Dubacq

Rabut

et al. 2023

Cells

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Homologous recombination (HR), an evolutionary conserved pathway, plays a paramount role(s) in genome plasticity. The pivotal HR step is the strand invasion/exchange of double-stranded DNA by a homologous single-stranded DNA (ssDNA) covered by RAD51. Thus, RAD51 plays a prime role in HR through this canonical catalytic strand invasion/exchange activity. The mutations in many HR genes cause oncogenesis. Surprisingly, despite its central role in HR, the invalidation of RAD51 is not classified as being cancer prone, constituting the “RAD51 paradox”. This suggests that RAD51 exercises other noncanonical roles that are independent of its catalytic strand invasion/exchange function. For example, the binding of RAD51 on ssDNA prevents nonconservative mutagenic DNA repair, which is independent of its strand exchange activity but relies on its ssDNA occupancy. At the arrested replication forks, RAD51 plays several noncanonical roles in the formation, protection, and management of fork reversal, allowing for the resumption of replication. RAD51 also exhibits noncanonical roles in RNA-mediated processes. Finally, RAD51 pathogenic variants have been described in the congenital mirror movement syndrome, revealing an unexpected role in brain development. In this review, we present and discuss the different noncanonical roles of RAD51, whose presence does not automatically result in an HR event, revealing the multiple faces of this prominent actor in genomic plasticity.

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A multi-functional role for the MCM8/9 helicase complex in maintaining fork integrity during replication stress

Cited by 15 publications

References 54 publications

Molecular functions of MCM8 and MCM9 and their associated pathologies

Molecular functions of MCM8 and MCM9 and their associated pathologies

An update on the Genetics of Premature ovarian insufficiency (POI) with special emphasis on mini chromosome maintenance (MCM)8 &9-A Short Communication

Noncanonical Roles of RAD51

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