title: Germline stem cell gene PIWIL2 mediates DNA repair through relaxation of chromatin.
abstract: DNA damage response (DDR) is an intrinsic barrier of cell to tumorigenesis initiated by genotoxic agents. However, the mechanisms underlying the DDR are not completely understood despite of extensive investigation. Recently, we have reported that ectopic expression of germline stem cell gene PIWIL2 is associated with tumor stem cell development, although the underlying mechanisms are largely unknown. Here we show that PIWIL2 is required for the repair of DNA-damage induced by various types of genotoxic agents. Upon ultraviolet (UV) irradiation, silenced PIWIL2 gene in normal human fibroblasts was transiently activated after treatment with UV light. This activation was associated with DNA repair, because Piwil2-deficienct mouse embryonic fibroblasts (mili(-/-) MEFs) were defective in cyclobutane pyrimidine dimers (CPD) repair after UV treatment. As a result, the UV-treated mili(-/-) MEFs were more susceptible to apoptosis, as characterized by increased levels of DNA damage-associated apoptotic proteins, such as active caspase-3, cleaved Poly (ADP-ribose) polymerase (PARP) and Bik. The impaired DNA repair in the mili(-/-) MEFs was associated with the reductions of histone H3 acetylation and chromatin relaxation, although the DDR pathway downstream chromatin relaxation appeared not to be directly affected by Piwil2. Moreover, guanine-guanine (Pt-[GG]) and double strand break (DSB) repair were also defective in the mili(-/-) MEFs treated by genotoxic chemicals Cisplatin and ionizing radiation (IR), respectively. The results indicate that Piwil2 can mediate DNA repair through an axis of Piwil2 → histone acetylation → chromatin relaxation upstream DDR pathways. The findings reveal a new role for Piwil2 in DNA repair and suggest that Piwil2 may act as a gatekeeper against DNA damage-mediated tumorigenesis.
authors: Department of Pathology, Ohio State University Medical Center, Columbus, Ohio, United States of America.
authors: De-Tao
authors: DT
authors: Yin
authors: Qien
authors: Q
authors: Wang
authors: Li
authors: L
authors: Chen
authors: Meng-Yao
authors: MY
authors: Liu
authors: Chunhua
authors: C
authors: Han
authors: Qingtao
authors: Q
authors: Yan
authors: Rulong
authors: R
authors: Shen
authors: Gang
authors: G
authors: He
authors: Wenrui
authors: W
authors: Duan
authors: Jian-Jian
authors: JJ
authors: Li
authors: Altaf
authors: A
authors: Wani
authors: Jian-Xin
authors: JX
authors: Gao
mesh_terms: D000107:Acetylation / Q000187:drug effects / Q000528:radiation effects; D000818:Animals; D060565:Argonaute Proteins / Q000172:deficiency / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D002460:Cell Line; D002843:Chromatin / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage / Q000235:genetics; D004260:DNA Repair / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D007259:Infrared Rays / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D013234:Stem Cells / Q000378:metabolism*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D060565:Argonaute Proteins; D002843:Chromatin; D006657:Histones; C486868:PIWIL2 protein, human; D002945:Cisplatin