DDK/Hsk1 phosphorylates and targets fission yeast histone deacetylase Hst4 for degradation to stabilize stalled DNA replication forks

eLife

Devyani Haldar¹  Shalini Aricthota² 

[1] Laboratory of Chromatin Biology and Epigenetics, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India;Laboratory of Chromatin Biology and Epigenetics, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, India;Graduate Studies, Manipal Academy of Higher Education, Manipal, India;

关键词: sirtuin;    H3K56ac;    replication fork;    Swi1;    timeless;    genome stability;    S. pombe;   

DOI  :  10.7554/eLife.70787

来源: eLife Sciences Publications, Ltd

【 摘 要 】

In eukaryotes, paused replication forks are prone to collapse, which leads to genomic instability, a hallmark of cancer. Dbf4-dependent kinase (DDK)/Hsk1Cdc7 is a conserved replication initiator kinase with conflicting roles in replication stress response. Here, we show that fission yeast DDK/Hsk1 phosphorylates sirtuin, Hst4 upon replication stress at C-terminal serine residues. Phosphorylation of Hst4 by DDK marks it for degradation via the ubiquitin ligase SCFpof3. Phosphorylation-defective hst4 mutant (4SA-hst4) displays defective recovery from replication stress, faulty fork restart, slow S-phase progression and decreased viability. The highly conserved fork protection complex (FPC) stabilizes stalled replication forks. We found that the recruitment of FPC components, Swi1 and Mcl1 to the chromatin is compromised in the 4SA-hst4 mutant, although whole cell levels increased. These defects are dependent upon H3K56ac and independent of intra S-phase checkpoint activation. Finally, we show conservation of H3K56ac-dependent regulation of Timeless, Tipin, and And-1 in human cells. We propose that degradation of Hst4 via DDK increases H3K56ac, changing the chromatin state in the vicinity of stalled forks facilitating recruitment and function of FPC. Overall, this study identified a crucial role of DDK and FPC in the regulation of replication stress response with implications in cancer therapeutics.

【 授权许可】

CC BY