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.checkpoint | histone methylation | MMSET D amage to DNA occurs continuously, threatening the integrity of our genetic material. The ability to repair DNA lesions is critical for proper organismal development and survival. In response to DNA damage or replication stress, a signal transduction cascade called the DNA damage response (DDR) is activated to maintain genomic integrity (1, 2). The ATM and ATR kinases are central components of the DDR. ATM is recruited and activated by the MRE11-RAD50-NBS1 complex at double-strand breaks (DSBs), where ATM phosphorylates the histone variant H2AX (3, 4). Phosphorylated H2AX then associates with the mediator protein MDC1, which leads to the activation of ubiquitination and sumoylation cascades required for the recruitment of the BRCA1 ubiquitin ligase and the mediator protein 53BP1 to promote DNA repair (5, 6). Unlike ATM, the ATR kinase is activated following its recruitment by its partner protein ATRIP to RPA-coated ssDNA regions generated at stalled or collapsed forks. RPA-ssDNA complexes also recruit the RAD17-RFC2-5 complex that loads the RAD1-RAD9-HUS1 (9-1-1) complex onto DNA. The 9-1-1 complex recruits RHINO (7) and the mediator protein TOPBP1 to further activate ATR (8, 9). ATM and ATR are known to control the phosphorylation of nearly 1,000 effector proteins involved in a wide number of cellular processes, such DNA repair, transcription, chromatin structure, splicing, metabolism, induction of apoptosis, and senescence.The importance of the DDR in human physiology is underscored by the observation that dysregulation of DNA repair pathways can lead to a range of human disorders exhibiting developmental defects, neurological defects, immunodeficiency, and cancer (2, 3). The developmental and neurological defects are likely due to the requirement for extremely accurate DNA repair during the rapid expansion of progenitor cells occurring during embryonic development and for the maintenance of the homeostasis of the nervous system.The number of syndromes associated with neurological and developmenta...

Deletions involving genes WHSC1 and LETM1 may be necessary, but are not sufficient to cause Wolf–Hirschhorn Syndrome

“…26,27 Histone modification is essential for the establishment and maintenance of transcriptional programs during development and gene dosage alterations of histone modifiers are a known cause of intellectual disability syndromes. 28 The HMT function of WHSC1 has been implicated in diverse biological processes, including early development, 29 cytokine signaling, 30 the DNA damage response 31,32 and class switch recombination. 33 In addition to its functional diversity, WHSC1 has a complex pattern of expression, with the potential to regulate multiple processes during development.…”

Wolf-Hirschhorn Syndrome (WHS) – Literature Review on the Features of the Syndrome

“…The genetics were not well developed at that moment, so no sooner than when Lejeune et al described the cri du chat syndrome as a partial deletion of chromosome 5, that it turned out the patient described by Hirschhorn and Cooper was characterized with other symptoms [1][2][3][4][5]. The vast majority of cases are caused by a deletion of 4p16.3 regio, especially among Wolf-Hirschhorn candidate genes or, so called, critical regions (WHSC1 and WHSC2) [1,3,6]. Small deletions are easier to diagnose than distal deletions [1].…”

“…WHSC1 is responsible for the regulation of methylation of histone H4 K20 residue, which is required for the junction of 53BP1 to sites of DNA damage. This leads to the thesis that Wolf-Hirschhorn syndrome might be the cause of DNA damage response (DDR) [6]. The importance of DDR is observed in the fact that the DNA repair impairment may lead to developmental defects, immunodeficiency, neurological problems and cancer [9,10].…”

“…The t(4;14)(p16.3;q32.3) chromosomal translocation (that also targets WHSC1 gene) results in the overproduction of WHSC1 protein in myelomas [6].…”

“…The recruitment is not fully understood yet, aside from the fact that WHSC1 plays a crucial role in DNA damage response, and is therefore involved in human development and neuronal homeostasis. Its deletion leads to increased levels of DNA damage [6].…”