title: RRM1 maintains centrosomal integrity via CHK1 and CDK1 signaling during replication stress.
abstract: DNA lesion-induced centrosomal abnormalities during the replication phase are relatively unknown. Here, we report that RNAi-mediated depletion of RRM1 induces cell-cycle arrest at the replication phase, along with severe DNA damage and centrosomal amplification. Interestingly, CHK1 depletion synergistically increased RRM1-depletion-induced centrosomal amplification. In response to hydroxyurea, CHK1 was delocalized from the centrosome by RRM1 depletion. Moreover, CDK1, which functions in centrosome separation and is inhibited by CHK1, was found to be essential for RRMI1-depletion-induced centrosomal amplification. Thus, we herein demonstrate that RRM1 preserves chromosomal stability via the CHK1- and CDK1-dependent stabilization of the centrosomal integrity at the replication stage.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Eun-Ran
authors.initials: ER
authors.lastname: Park
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Hyun-Yoo
authors.initials: HY
authors.lastname: Joo
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Yan Nan
authors.initials: YN
authors.lastname: Shen
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hong
authors.affiliation: Division of Radiation Effect, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Chun Ho
authors.initials: CH
authors.lastname: Kim
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea.
authors.forename: Rachana
authors.initials: R
authors.lastname: Singh
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: khlee@kirams.re.kr.
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological & Medical Sciences, Seoul 139-706, Republic of Korea. Electronic address: hjshin@kcch.re.kr.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Shin
mesh_terms: D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D018385:Centrosome / Q000378:metabolism / Q000502:physiology*; D000071877:Checkpoint Kinase 1; D019925:Cyclin A / Q000378:metabolism; D019926:Cyclin B / Q000378:metabolism; D004249:DNA Damage; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006367:HeLa Cells; D006801:Humans; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D012262:Ribonucleoside Diphosphate Reductase; D015398:Signal Transduction; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D019925:Cyclin A; D019926:Cyclin B; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; C475286:RRM1 protein, human; D012262:Ribonucleoside Diphosphate Reductase; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1; D016203:CDC2 Protein Kinase
keywords: Centrosome integrity; DNA damage; RRM1; Replication fork stalling; Tumor suppressor; Tumorigenesis