Open AccessLRR1-mediated replisome disassembly promotes DNA replication by recycling replisome components
Author(s) -
Yilin Fan,
Marielle S. Köberlin,
Nalin Ratnayeke,
Chad Liu,
Madhura Deshpande,
Jeannine Gerhardt,
Tobias Meyer
Publication year - 2021
Publication title -
the journal of cell biology/the journal of cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.414
H-Index - 380
eISSN - 1540-8140
pISSN - 0021-9525
DOI - 10.1083/jcb.202009147
Subject(s) - replisome , biology , microbiology and biotechnology , helicase , pre replication complex , chromatin , dna replication , control of chromosome duplication , eukaryotic dna replication , g2 m dna damage checkpoint , mitosis , dna replication factor cdt1 , genetics , cell cycle , dna , cell cycle checkpoint , gene , rna
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.