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

Abstract

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.

Abstract

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.