Genome-wide reinforcement of cohesin binding at pre-existing cohesin sites in response to ionizing radiation in human cells.
The cohesin complex plays a central role in genome maintenance by regulation of chromosome segregation in mitosis and DNA damage response (DDR) in other phases of the cell cycle. The ATM/ATR phosphorylates SMC1 and SMC3, two core components of the cohesin complex to regulate checkpoint signaling and DNA repair. In this report, we show that the genome-wide binding of SMC1 and SMC3 after ionizing radiation (IR) is enhanced by reinforcing pre-existing cohesin binding sites in human cancer cells. We demonstrate that ATM and SMC3 phosphorylation at Ser(1083) regulate this process. We also demonstrate that acetylation of SMC3 at Lys(105) and Lys(106) is induced by IR and this induction depends on the acetyltransferase ESCO1 as well as the ATM/ATR kinases. Consistently, both ESCO1 and SMC3 acetylation are required for intra-S phase checkpoint and cellular survival after IR. Although both IR-induced acetylation and phosphorylation of SMC3 are under the control of ATM/ATR, the two forms of modification are independent of each other and both are required to promote reinforcement of SMC3 binding to cohesin sites. Thus, SMC3 modifications is a mechanism for genome-wide reinforcement of cohesin binding in response to DNA damage response in human cells and enhanced cohesion is a downstream event of DDR.
Kim
Beom-Jun
BJ
Center for Molecular Discovery, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Li
Yehua
Y
Zhang
Jinglan
J
Xi
Yuanxin
Y
Li
Yumei
Y
Yang
Tao
T
Jung
Sung Yun
SY
Pan
Xuewen
X
Chen
Rui
R
Li
Wei
W
Wang
Yi
Y
Qin
Jun
J
D000107:Acetylation / Q000528:radiation effects; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001665:Binding Sites / Q000528:radiation effects; D018797:Cell Cycle Proteins / Q000378:metabolism*; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism / Q000528:radiation effects; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded / Q000528:radiation effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D015894:Genome, Human / Q000528:radiation effects*; D006367:HeLa Cells; D006801:Humans; D010766:Phosphorylation / Q000528:radiation effects; D011485:Protein Binding / Q000528:radiation effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1
D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D011508:Chondroitin Sulfate Proteoglycans; D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D017346:Protein Serine-Threonine Kinases; D025521:Tumor Suppressor Proteins; D000097722:Cohesins; D000098550:Structural Maintenance of Chromosome Protein 1; C492318:SMC3 protein, human; C576324:ATM protein, human