title: Wolf-Hirschhorn syndrome candidate 1 is involved in the cellular response to DNA damage.
abstract: Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with growth retardation, mental retardation, and immunodeficiency resulting from a hemizygous deletion of the short arm of chromosome 4, called the WHS critical region (WHSC). The WHSC1 gene is located in this region, and its loss is believed to be responsible for a number of WHS characteristics. We identified WHSC1 in a genetic screen for genes involved in responding to replication stress, linking Wolf-Hirschhorn syndrome to the DNA damage response (DDR). Here, we report that the WHSC1 protein is a member of the DDR pathway. WHSC1 localizes to sites of DNA damage and replication stress and is required for resistance to many DNA-damaging and replication stress-inducing agents. Through its SET domain, WHSC1 regulates the methylation status of the histone H4 K20 residue and is required for the recruitment of 53BP1 to sites of DNA damage. We propose that Wolf-Hirschhorn syndrome results from a defect in the DDR.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute, Division of Genetics, Brigham and Women's Hospital, Harvard University Medical School, Boston, MA 02115, USA.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Hajdu
authors.forename: Alberto
authors.initials: A
authors.lastname: Ciccia
authors.forename: Susanna M
authors.initials: SM
authors.lastname: Lewis
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
mesh_terms: D045744:Cell Line, Tumor; D064447:Checkpoint Kinase 2; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D020868:Gene Silencing / Q000187:drug effects; D011495:Histone-Lysine N-Methyltransferase / Q000172:deficiency / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008239:Lysine / Q000378:metabolism; D008745:Methylation / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051716:Replication Protein A / Q000378:metabolism; D012097:Repressor Proteins / Q000172:deficiency / Q000378:metabolism*; D013312:Stress, Physiological / Q000187:drug effects; D000071857:Tumor Suppressor p53-Binding Protein 1; D054877:Wolf-Hirschhorn Syndrome / Q000378:metabolism* / Q000473:pathology*
chemical_list: C468783:H2AX protein, human; D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D051716:Replication Protein A; D012097:Repressor Proteins; C498301:TP53BP1 protein, human; D000071857:Tumor Suppressor p53-Binding Protein 1; D011495:Histone-Lysine N-Methyltransferase; C419586:NSD2 protein, human; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases; D008239:Lysine; D006918:Hydroxyurea