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

The minichromosome maintenance (MCM) 8/9 helicase is a AAA + complex involved in DNA replication-associated repair. Despite high sequence homology to the MCM2-7 helicase, a precise cellular role for MCM8/9 has remained elusive. We have interrogated the DNA synthesis ability and replication fork stab...

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Published in:Nature communications 2022-08, Vol.13 (1), p.5090-5090, Article 5090
Main Authors: Griffin, Wezley C., McKinzey, David R., Klinzing, Kathleen N., Baratam, Rithvik, Eliyapura, Achini, Trakselis, Michael A.
Format: Article
Language:English
Subjects:
13/1
13/31
13/44
13/89
14/1
14/19
14/34
14/63
631/45/147
631/80
BRCA1 protein
Breast cancer
Cell cycle
Cell division
Degradation
Deoxyribonucleic acid
DNA
DNA biosynthesis
DNA helicase
DNA Repair
DNA Replication
Genomes
Genomic Instability
Homology
Humanities and Social Sciences
Humans
Infertility
Integrity
Minichromosome Maintenance Proteins - genetics
multidisciplinary
Mutation
Nucleotide sequence
Proteins
Recombination
Replication
Science
Science (multidisciplinary)
Stalling
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Summary:The minichromosome maintenance (MCM) 8/9 helicase is a AAA + complex involved in DNA replication-associated repair. Despite high sequence homology to the MCM2-7 helicase, a precise cellular role for MCM8/9 has remained elusive. We have interrogated the DNA synthesis ability and replication fork stability in cells lacking MCM8 or 9 and find that there is a functional partitioning of MCM8/9 activity between promoting replication fork progression and protecting persistently stalled forks. The helicase function of MCM8/9 aids in normal replication fork progression, but upon persistent stalling, MCM8/9 directs additional downstream stabilizers, including BRCA1 and Rad51, to protect forks from excessive degradation. Loss of MCM8 or 9 slows the overall replication rate and allows for excessive nascent strand degradation, detectable by increased markers of genomic damage. This evidence defines multifunctional roles for MCM8/9 in promoting normal replication fork progression and genome integrity following stress. The MCM8/9 helicase has been implicated in DNA recombination processes with mutations in these genes causative for infertility and cancer. Here, the authors show that MCM8/9 aids normal fork progression and also stabilizes persistently stalled forks, acting upstream of RAD51 and BRCA1.
ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-32583-8