title: Microcephalin is a DNA damage response protein involved in regulation of CHK1 and BRCA1.
abstract: Microcephalin (MCPH1) is the first gene identified among at least six loci that contribute to the autosomal recessive disease, primary microcephaly. MCPH1, like NFBD1/MDC1, 53BP1, and BRCA1, encodes a protein with twin carboxyl-terminal BRCT domains (PTCB). Here, we report that Mcph1 forms ionizing radiation-induced foci. Down-regulation of Mcph1, like other PTCBs, by siRNA, impairs ionizing radiation-induced intra-S-phase and G(2)/M checkpoints. Inhibition of the expression of Mcph1 decreases both protein and transcript levels of endogenous Brca1 but not exogenous Brca1. Mcph1 inhibition also decreases both endogenous and heterologous Chk1 transcripts and protein. We conclude that Mcph1 is involved in DNA damage-induced cellular responses, and we propose that regulation of Brca1 and/or Chk1 by Mcph1 may contribute to these cellular responses.
authors.affiliation: Department of Pathology, School of Medicine, Yale University, 310 Cedar Street, New Haven, CT 06510, USA. xaxu@coh.org
authors.forename: Xingzhi
authors.initials: X
authors.lastname: Xu
authors.forename: Juhie
authors.initials: J
authors.lastname: Lee
authors.forename: David F
authors.initials: DF
authors.lastname: Stern
mesh_terms: D019313:BRCA1 Protein / Q000378:metabolism*; D015152:Blotting, Northern; D015153:Blotting, Western; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D003598:Cytoskeletal Proteins; D004247:DNA / Q000378:metabolism; D004249:DNA Damage; D015536:Down-Regulation; D016195:G2 Phase; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D008938:Mitosis; D009419:Nerve Tissue Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D011839:Radiation, Ionizing
chemical_list: D019313:BRCA1 Protein; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D006657:Histones; C460645:MCPH1 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D004247:DNA; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1