Loss of Smu1 function de-represses DNA replication and over-activates ATR-dependent replication checkpoint

Laifeng Ren; Yao Liu; Liandi Guo; Haibin Wang; Lei Ma; Ming Zeng; Xin Shao; Chunlei Yang; Yaxiong Tang; Lei Wang; Cong Liu; Mingyuan Li

doi:10.1016/j.bbrc.2013.05.072

Loss of Smu1 function de-represses DNA replication and over-activates ATR-dependent replication checkpoint

Biochem Biophys Res Commun. 2013 Jun 28;436(2):192-8. doi: 10.1016/j.bbrc.2013.05.072. Epub 2013 May 29.

Authors

Laifeng Ren¹, Yao Liu, Liandi Guo, Haibin Wang, Lei Ma, Ming Zeng, Xin Shao, Chunlei Yang, Yaxiong Tang, Lei Wang, Cong Liu, Mingyuan Li

Affiliation

¹ Department of Microbiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, PR China.

PMID: 23727573
DOI: 10.1016/j.bbrc.2013.05.072

Abstract

Smu1 is an evolutionarily conserved gene that encodes a member of the WD40-repeat protein family. Disruption of Smu1 function leads to multiple cellular defects including chromosomal instability, aberrant DNA replication and alternative RNA splicing events. In this paper, we show that Smu1 is a chromatin-bound protein that functions as a negative regulator of DNA replication. Knockdown of Smu1 gene expression promotes excessive incorporation of dNTP analogue, implicating the acceleration of DNA synthesis. Smu1-silenced cells show an excessive activation of replication checkpoint in response to ultraviolate (UV) or hydroxyurea treatment, indicating that abnormal stimulation of DNA replication leads to instability of genomic structure. Hence, we propose that Smu1 participates in the protection of genomic integrity by negatively regulating the process of DNA synthesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / pharmacology
Ataxia Telangiectasia Mutated Proteins
Blotting, Western
Cell Cycle Proteins / metabolism*
Cell Line, Tumor
Cell Survival / drug effects
Cell Survival / genetics
Cell Survival / radiation effects
Chromatin / genetics
Chromatin / metabolism
Chromosomal Proteins, Non-Histone / genetics
Chromosomal Proteins, Non-Histone / metabolism*
DNA Replication*
Dose-Response Relationship, Drug
Dose-Response Relationship, Radiation
Flow Cytometry
G2 Phase Cell Cycle Checkpoints*
HEK293 Cells
Humans
Hydroxyurea / pharmacology
Microscopy, Fluorescence
Protein Binding
Protein Serine-Threonine Kinases / metabolism*
RNA Interference
Ultraviolet Rays

Substances

Antineoplastic Agents
Cell Cycle Proteins
Chromatin
Chromosomal Proteins, Non-Histone
Smu1 protein, human
ATR protein, human
Ataxia Telangiectasia Mutated Proteins
Protein Serine-Threonine Kinases
Hydroxyurea