A kinase-independent function of c-Abl in promoting proteolytic destruction of damaged DNA binding proteins.
Damaged DNA binding proteins (DDBs) play a critical role in the initial recognition of UV-damaged DNA and mediate recruitment of nucleotide excision repair factors. Previous studies identified DDB2 as a target of the CUL-4A ubiquitin ligase. However, the biochemical mechanism governing DDB proteolysis and its underlying physiological function in the removal of UV-induced DNA damage are largely unknown. Here, we report that the c-Abl nonreceptor tyrosine kinase negatively regulates the repair of UV-induced photolesions on genomic DNA. Biochemical studies revealed that c-Abl promotes CUL-4A-mediated DDB ubiquitination and degradation in a manner that does not require its tyrosine kinase activity both under normal growth conditions and following UV irradiation. Moreover, c-Abl activates DDB degradation in part by alleviating the inhibitory effect of CAND1/TIP120A on CUL-4A. These results revealed a kinase-independent function of c-Abl in a ubiquitin-proteolytic pathway that regulates the damage recognition step of nucleotide excision repair.
Chen
Xiaoai
X
Department of Pathology and Laboratory Medicine, Weill Medical College and Graduate School of Medical Sciences of Cornell University, New York, New York 10021, USA.
Zhang
Jianxuan
J
Lee
Jennifer
J
Lin
Patrick S
PS
Ford
James M
JM
Zheng
Ning
N
Zhou
Pengbo
P
D000818:Animals; D002478:Cells, Cultured; D044842:Cullin Proteins / Q000378:metabolism; D004249:DNA Damage; D004260:DNA Repair / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D051379:Mice; D016315:Proto-Oncogene Proteins c-abl / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects
C491940:Cul4a protein, mouse; D044842:Cullin Proteins; D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D034741:RNA, Small Interfering; D014157:Transcription Factors; D025801:Ubiquitin; D016315:Proto-Oncogene Proteins c-abl