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PP2AC alpha deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells
Bo Liu1,2; Lin Lin2,6; Saima Riazuddin1; Ahmed Zubair1; Li Wang3; Li-Jun Di3; Rui Li5,6; Ting-Ting Dong6,7; Chu-Xia Deng4; Wei-Min Tong4
2019-01-30
Source PublicationINTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
ISSN1357-2725
Volume109Pages:40-58
Abstract

The role of protein phosphatase 2AC alpha (PP2AC alpha) in brain development is poorly understood. To understand the function of PP2AC alpha in neurogenesis, we inactivated Pp2ac alpha gene in the central nervous system (CNS) of mice by Cre/LoxP system and generated the PP2AC alpha deficient mice (designated as the Pp2ac alpha(-/-) mice). PP2AC alpha deletion results in DNA damage in neuroprogenitor cells (NPCs), which impairs memory formation and cortical neurogenesis. We first identify that PP2AC alpha can directly associate with Ataxia telangiectasia mutant kinase (ATM) and Ataxia telangiectasia/Rad3-related kinase (ATR) in neocortex and NPCs. Importantly, the P53 and hypermethylated in cancer 1 (HIC1) function complex, the newly found down-stream executor of the ATR/ATM cascade, will be translocated into nuclei and interact with homeodomain interacting protein kinase 2 (HIPK2) to respond to DNA damage. Notably, HICI plays a direct transcriptional regulatory role in HIPK2 gene expression. The interplay among P53, HIC1 and HIPK2 maintains DNA stability in neuroprogenitor cells. Taken together, our findings highlight a new role of PP2AC alpha in regulating early neurogenesis through maintaining DNA stability in neuroprogenitor cells. The P53/HIC/HIPK2 regulation loop, directly targeted by the ATR/ATM cascade, is involved in DNA repair in neuroprogenitor cells.

KeywordProtein Phosphorylation Brain Development Dna Damage Stem Cell Signaling Cascade
DOI10.1016/j.biocel.2019.01.021
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000462103900006
PublisherPERGAMON-ELSEVIER SCIENCE LTD, THE BOULEVARD, LANGFORD LANE, KIDLINGTON, OXFORD OX5 1GB, ENGLAND
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Cited Times [WOS]:0   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Corresponding AuthorBo Liu; Chu-Xia Deng; Wei-Min Tong
Affiliation1.Department of Otorhinolaryngology Head&Neck Surgery, University of Maryland School of Medicine, Baltimore, USA
2.University of Macau, Macau, China
3.Branch of Cancer Research, Jones Hopkins University, Baltimore, USA
4.National Institute of Neurological Disorders and Stroke, National Institute of Heath, Bethesda, USA
5.Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
6.Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Sciences. Beijing, China
7.China Agricultural University, Beijing, China
First Author AffilicationUniversity of Macau
Corresponding Author AffilicationUniversity of Macau
Recommended Citation
GB/T 7714
Bo Liu,Lin Lin,Saima Riazuddin,et al. PP2AC alpha deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells[J]. INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY,2019,109:40-58.
APA Bo Liu.,Lin Lin.,Saima Riazuddin.,Ahmed Zubair.,Li Wang.,...&Wei-Min Tong.(2019).PP2AC alpha deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells.INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY,109,40-58.
MLA Bo Liu,et al."PP2AC alpha deficiency impairs early cortical development through inducing DNA damage in neuroprojenitor cells".INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY 109(2019):40-58.
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