LRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.

TitleLRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components.
Publication TypeJournal Article
Year of Publication2021
AuthorsFan Y, Köberlin MS, Ratnayeke N, Liu C, Deshpande M, Gerhardt J, Meyer T
JournalJ Cell Biol
Date Published2021 08 02
KeywordsAtaxia Telangiectasia Mutated Proteins, Cell Cycle Proteins, Cell Line, Tumor, Cell Proliferation, Checkpoint Kinase 1, Chromatin Assembly and Disassembly, DNA, DNA Helicases, Humans, Microscopy, Fluorescence, Neoplasms, Protein Binding, Protein-Tyrosine Kinases, Repressor Proteins, S Phase, Time Factors

After two converging DNA replication forks meet, active replisomes are disassembled and unloaded from chromatin. A key process in replisome disassembly is the unloading of CMG helicases (CDC45-MCM-GINS), which is initiated in Caenorhabditis elegans and Xenopus laevis by the E3 ubiquitin ligase CRL2LRR1. Here, we show that human cells lacking LRR1 fail to unload CMG helicases and accumulate increasing amounts of chromatin-bound replisome components as cells progress through S phase. Markedly, we demonstrate that the failure to disassemble replisomes reduces the rate of DNA replication increasingly throughout S phase by sequestering rate-limiting replisome components on chromatin and blocking their recycling. Continued binding of CMG helicases to chromatin during G2 phase blocks mitosis by activating an ATR-mediated G2/M checkpoint. Finally, we provide evidence that LRR1 is an essential gene for human cell division, suggesting that CRL2LRR1 enzyme activity is required for the proliferation of cancer cells and is thus a potential target for cancer therapy.

Alternate JournalJ Cell Biol
PubMed ID34037657
PubMed Central IDPMC8160578
Grant ListR35 GM127026 / GM / NIGMS NIH HHS / United States