Comparative phosphoproteomic analysis of checkpoint recovery identifies new regulators of the DNA damage response.

Abstract:

:How cells recover from a DNA damage-induced arrest is currently poorly understood. We performed large-scale quantitative phosphoproteomics to identify changes in protein phosphorylation that occurred during recovery from arrest in the G2 phase of the cell cycle caused by DNA damage. We identified 154 proteins that were differentially phosphorylated, and systematic depletion of each of these differentially phosphorylated proteins by small interfering RNA (siRNA) identified at least 10 potential regulators of recovery. Astrin, a protein associated with the mitotic spindle, was among the potential regulators of recovery. We found that astrin controlled the abundance of the cell cycle regulator p53 during DNA damage-induced arrest. Cells in which astrin was depleted had decreased murine double minute 2 (MDM2) abundance and increased p53 at the later stages of the DNA damage response. Astrin was required for continued expression of genes encoding proteins that promote cell cycle progression in arrested cells. Thus, by controlling p53 abundance in cells recovering from DNA damage, astrin maintains the cells in a state competent to resume the cell cycle.

journal_name

Sci Signal

journal_title

Science signaling

authors

Halim VA,Alvarez-Fernández M,Xu YJ,Aprelia M,van den Toorn HW,Heck AJ,Mohammed S,Medema RH

doi

10.1126/scisignal.2003664

subject

Has Abstract

pub_date

2013-04-23 00:00:00

pages

rs9

issue

272

eissn

1945-0877

issn

1937-9145

pii

6/272/rs9

journal_volume

6

pub_type

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