Regulation of DNA damage responses and cell cycle progression by hMOB2

Valenti Gomez; Ramazan Gundogdu; Marta Gomez; Lily Hoa; Neelam Panchal; Mark O'Driscoll; Alexander Hergovich

doi:10.1016/j.cellsig.2014.11.016

Regulation of DNA damage responses and cell cycle progression by hMOB2

Cell Signal. 2015 Feb;27(2):326-39. doi: 10.1016/j.cellsig.2014.11.016. Epub 2014 Nov 21.

Authors

Valenti Gomez¹, Ramazan Gundogdu¹, Marta Gomez¹, Lily Hoa¹, Neelam Panchal¹, Mark O'Driscoll², Alexander Hergovich³

Affiliations

¹ UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom.
² Genome Damage and Stability Centre, University of Sussex, BN1 9RH, Brighton, United Kingdom.
³ UCL Cancer Institute, University College London, WC1E 6BT, London, United Kingdom. Electronic address: a.hergovich@ucl.ac.uk.

Abstract

Mps one binder proteins (MOBs) are conserved regulators of essential signalling pathways. Biochemically, human MOB2 (hMOB2) can inhibit NDR kinases by competing with hMOB1 for binding to NDRs. However, biological roles of hMOB2 have remained enigmatic. Here, we describe novel functions of hMOB2 in the DNA damage response (DDR) and cell cycle regulation. hMOB2 promotes DDR signalling, cell survival and cell cycle arrest after exogenously induced DNA damage. Under normal growth conditions in the absence of exogenously induced DNA damage hMOB2 plays a role in preventing the accumulation of endogenous DNA damage and a subsequent p53/p21-dependent G1/S cell cycle arrest. Unexpectedly, these molecular and cellular phenotypes are not observed upon NDR manipulations, indicating that hMOB2 performs these functions independent of NDR signalling. Thus, to gain mechanistic insight, we screened for novel binding partners of hMOB2, revealing that hMOB2 interacts with RAD50, facilitating the recruitment of the MRE11-RAD50-NBS1 (MRN) DNA damage sensor complex and activated ATM to DNA damaged chromatin. Taken together, we conclude that hMOB2 supports the DDR and cell cycle progression.

Keywords: Cell cycle checkpoint activation; Cell cycle progression; DNA damage response signalling; MRE11–RAD50–NBS1 protein complex; Mps one binder 2; p53 tumour suppressor protein.

Publication types

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

MeSH terms

Animals
Antibiotics, Antineoplastic / pharmacology
Ataxia Telangiectasia Mutated Proteins / metabolism
COS Cells
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Chlorocebus aethiops
Chromosomal Proteins, Non-Histone / metabolism
Cyclin-Dependent Kinase Inhibitor p21 / metabolism
DNA Damage*
Doxorubicin / pharmacology
G1 Phase Cell Cycle Checkpoints / drug effects
G1 Phase Cell Cycle Checkpoints / radiation effects
Humans
Nerve Tissue Proteins / antagonists & inhibitors
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism*
Nuclear Proteins / metabolism
Phosphorylation / drug effects
Phosphorylation / radiation effects
RNA, Small Interfering / metabolism
Radiation, Ionizing
S Phase Cell Cycle Checkpoints / drug effects
S Phase Cell Cycle Checkpoints / radiation effects
Signal Transduction / drug effects
Signal Transduction / radiation effects
Tumor Suppressor Protein p53 / antagonists & inhibitors
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

Antibiotics, Antineoplastic
Cell Cycle Proteins
Chromosomal Proteins, Non-Histone
Cyclin-Dependent Kinase Inhibitor p21
MOB2 protein, human
NBN protein, human
Nerve Tissue Proteins
Nuclear Proteins
RNA, Small Interfering
TP53 protein, human
Tumor Suppressor Protein p53
structural maintenance of chromosome protein 1
Doxorubicin
Ataxia Telangiectasia Mutated Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding