Mdt1/ASCIZ: a new DNA damage response protein family.
DNA damage response pathways are crucial for genome stability and prevention of cancer and are overall remarkably conserved from yeast to mammals. Two novel DNA damage response proteins, yeast Mdt1 (Modifier of DNA damage tolerance 1) and human ASCIZ (ATM/ATR-substrate Chk2-interacting Zn(2+)-finger protein), were recently identified based on their interactions with the N-terminal FHA domains of the conserved checkpoint kinases Rad53 and Chk2, respectively, and ASCIZ was subsequently re-isolated as an ATM-interacting protein (ATMIN). Mdt1 and ASCIZ share remarkable sequence similarity (36% highly conserved residues, 17% identity) and extended SQ/TQ cluster domains (SCDs) typical of DNA damage response proteins. However, despite their structural similarities and conserved interactions with the checkpoint machinery, the two proteins seem to respond to different DNA lesions: the strongest phenotypes of ASCIZ deficiency are increased sensitivity to DNA base damaging agents and altered immunoglobulin gene diversification following enzyme-induced base damage in B lymphocytes, whereas absence of Mdt1 leads to hypersensitivity to 3'-blocked DNA double-strand breaks and inefficient recombinational maintenance of telomeres. The Mdt1/ASCIZ family may function as structurally related scaffolds that facilitate efficient DNA repair, albeit with diverged lesion specificity.
Heierhorst
Jörg
J
St. Vincent's Institute of Medical Research and Department of Medicine St. Vincent's Hospital, The University of Melbourne, Fitzroy, Victoria, Australia. jheierhorst@svi.edu.au
D000595:Amino Acid Sequence; D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins; D001402:B-Lymphocytes / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D010088:Oxidoreductases; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases