An HDAC1-binding domain within FATS bridges p21 turnover to radiation-induced tumorigenesis.
There is a gap between the initial formation of cells carrying radiation-induced genetic damage and their contribution to cancer development. Herein, we reveal a previously uncharacterized gene FATS through a genome-wide approach and demonstrate its essential role in regulating the abundance of p21 in surveillance of genome integrity. A large exon coding the NH2-terminal domain of FATS, deleted in spontaneous mouse lymphomas, is much more frequently deleted in radiation-induced mouse lymphomas. Its human counterpart is a fragile site gene at a previously identified loss of heterozygosity site. FATS is essential for maintaining steady-state level of p21 protein and sustaining DNA damage checkpoint. Furthermore, the NH2-terminal FATS physically interacts with histone deacetylase 1 (HDAC1) to enhance the acetylation of endogenous p21, leading to the stabilization of p21. Our results reveal a molecular linkage between p21 abundance and radiation-induced carcinogenesis.
Li
Z
Z
Department of Biochemistry and Molecular Biology, Key Laboratory of Ministry of Education for Breast Cancer Prevention and Treatment, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. zhengli@tijmu.edu.cn
Zhang
Q
Q
Mao
J-H
JH
Weise
A
A
Mrasek
K
K
Fan
X
X
Zhang
X
X
Liehr
T
T
Lu
K H
KH
Balmain
A
A
Cai
W-W
WW
D000107:Acetylation; D000818:Animals; D001665:Binding Sites; D002455:Cell Division; D043283:Chromosome Fragile Sites; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism*; D004249:DNA Damage; D016195:G2 Phase; D056284:Histone Deacetylase 1 / Q000502:physiology*; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D009381:Neoplasms, Radiation-Induced / Q000209:etiology*; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D054875:Ubiquitination
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D025521:Tumor Suppressor Proteins; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1