Tousled-like kinases stabilize replication forks and show synthetic lethality with checkpoint and PARP inhibitors.

ABSTRACT: DNA sequence and epigenetic information embedded in chromatin must be faithfully duplicated and transmitted to daughter cells during cell division. However, how chromatin assembly and DNA replication are integrated remains unclear. We examined the contribution of the Tousled-like kinases 1 and 2 (TLK1/TLK2) to chromatin assembly and maintenance of replication fork integrity. We show that TLK activity is required for DNA replication and replication-coupled nucleosome assembly and that lack of TLK activity leads to replication fork stalling and the accumulation of single-stranded DNA, a phenotype distinct from ASF1 depletion. Consistent with these results, sustained TLK depletion gives rise to replication-dependent DNA damage and p53-dependent cell cycle arrest in G₁. We find that

SUBMITTER: Lee SB 

PROVIDER: S-EPMC6082654 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature