RRC ID 52507
Author Sunatani Y, Kamdar RP, Sharma MK, Matsui T, Sakasai R, Hashimoto M, Ishigaki Y, Matsumoto Y, Iwabuchi K.
Title Caspase-mediated cleavage of X-ray repair cross-complementing group 4 promotes apoptosis by enhancing nuclear translocation of caspase-activated DNase.
Journal Exp Cell Res
Abstract X-ray repair cross-complementing group 4 (XRCC4), a repair protein for DNA double-strand breaks, is cleaved by caspases during apoptosis. In this study, we examined the role of XRCC4 in apoptosis. Cell lines, derived from XRCC4-deficient M10 mouse lymphoma cells and stably expressing wild-type XRCC4 or caspase-resistant XRCC4, were established and treated with staurosporine (STS) to induce apoptosis. In STS-induced apoptosis, expression of wild-type, but not caspase-resistant, XRCC4 in XRCC4-deficient cells enhanced oligonucleosomal DNA fragmentation and the appearance of TUNEL-positive cells by promoting nuclear translocation of caspase-activated DNase (CAD), a major nuclease for oligonucleosomal DNA fragmentation. CAD activity is reportedly regulated by the ratio of two inhibitor of CAD (ICAD) splice variants, ICAD-L and ICAD-S mRNA, which, respectively, produce proteins with and without the ability to transport CAD into the nucleus. The XRCC4-dependent promotion of nuclear import of CAD in STS-treated cells was associated with reduction of ICAD-S mRNA and protein, and enhancement of phosphorylation and nuclear import of serine/arginine-rich splicing factor (SRSF) 1. These XRCC4-dependent, apoptosis-enhancing effects were canceled by depletion of SRSF1 or SR protein kinase (SRPK) 1. In addition, overexpression of SRSF1 in XRCC4-deficient cells restored the normal level of apoptosis, suggesting that SRSF1 functions downstream of XRCC4 in activating CAD. This XRCC4-dependent, SRPK1/SRSF1-mediated regulatory mechanism was conserved in apoptosis in Jurkat human leukemia cells triggered by STS, and by two widely used anti-cancer agents, Paclitaxel and Vincristine. These data imply that the level of XRCC4 expression could be used to predict the effects of apoptosis-inducing drugs in cancer treatment.
Volume 362(2)
Pages 450-460
Published 2018-1-15
DOI 10.1016/j.yexcr.2017.12.009
PII S0014-4827(17)30663-8
PMID 29233683
MeSH Animals Apoptosis / drug effects* Cell Nucleus / genetics DNA Fragmentation / drug effects DNA Repair / genetics DNA-Binding Proteins / genetics* Deoxyribonucleases / genetics Gene Expression Regulation, Neoplastic Humans Jurkat Cells Mice Neoplasms / drug therapy Neoplasms / genetics* Neoplasms / pathology Paclitaxel / pharmacology Protein Serine-Threonine Kinases / genetics* Serine-Arginine Splicing Factors / genetics* Signal Transduction / drug effects Staurosporine / pharmacology Vincristine / pharmacology
IF 3.383
Times Cited 1
Human and Animal Cells L5178Y(RCB0135)