The histone demethylase LSD1/KDM1A promotes the DNA damage response.
Histone demethylation is known to regulate transcription, but its role in other processes is largely unknown. We report a role for the histone demethylase LSD1/KDM1A in the DNA damage response (DDR). We show that LSD1 is recruited directly to sites of DNA damage. H3K4 dimethylation, a major substrate for LSD1, is reduced at sites of DNA damage in an LSD1-dependent manner. The E3 ubiquitin ligase RNF168 physically interacts with LSD1 and we find this interaction to be important for LSD1 recruitment to DNA damage sites. Although loss of LSD1 did not affect the initial formation of pH2A.X foci, 53BP1 and BRCA1 complex recruitment were reduced upon LSD1 knockdown. Mechanistically, this was likely a result of compromised histone ubiquitylation preferentially in late S/G2. Consistent with a role in the DDR, knockdown of LSD1 resulted in moderate hypersensitivity to γ-irradiation and increased homologous recombination. Our findings uncover a direct role for LSD1 in the DDR and place LSD1 downstream of RNF168 in the DDR pathway.
Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University in St. Louis, St. Louis, MO 63110.
Nima
N
Mosammaparast
Haeyoung
H
Kim
Benoit
B
Laurent
Yu
Y
Zhao
Hui Jun
HJ
Lim
Mona C
MC
Majid
Sebastian
S
Dango
Yuying
Y
Luo
Kristina
K
Hempel
Mathew E
ME
Sowa
Steven P
SP
Gygi
Hanno
H
Steen
J Wade
JW
Harper
Bruce
B
Yankner
Yang
Y
Shi
D000818:Animals; D019313:BRCA1 Protein / Q000378:metabolism; D045744:Cell Line, Tumor; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D057809:HEK293 Cells; D006367:HeLa Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D034622:RNA Interference; D034741:RNA, Small Interfering; D011836:Radiation Tolerance; D016196:S Phase / Q000235:genetics; D000071857:Tumor Suppressor p53-Binding Protein 1; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D056466:Histone Demethylases; C495195:KDM1A protein, human; C535210:RNF168 protein, human; D044767:Ubiquitin-Protein Ligases