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CHD2

Role of Chd2 in DNA Damage Response Signaling and Tumorigenesis (2009) Chd1 and Chd2 are separated by A + T Hook motif (HMG1) for DNA binding Chd2 mutant created by gene trap- inserting sequence between exons 27 and 28 resulting in Chd2-geo fusion protein containing first 1,198 amino acids of WT-Chd2 (1,827aa) In homozygous mutants, small amount of WT-Chd2 still expressed and was found to interact with the truncated Chd2 (tChd2). This could mean that tChd2 acts in a hypomorphic (mutant has reduced activity) or dominant negative (mutant antagonizes or competes with wild-type activity) manner, possibly sequestering WT-Chd2 in cytoplasmic or competing for binding partners or sites. The possibility of a gain-of-function activity by tChd2 cannot be ruled out. Chd2 mutants are defective in differentiation of hematopoetic stem cells Chd2 mutants have a high incidence of lymphoma generation Chd2 mutants have defects in DNA damage-induced H2AX signaling Conclusions: Chd2 plays an important role in hematopoetic and lymphoid development. It could possibly be a tumor suppressor and act in DNA damage response by removal of H2AX after repair is finished

Chd2 Affects the Repair of X-Ray and UV-Induced DNA Damage (2012) Same group as previous to study Chd2 and DNA damage response This time, they used a gene trap to create a truncated Chd2 missing part of the N-terminal end (cassette inserted between exon 1 and 2) Conclusions: Chd2 protein could modulate DNA repair either by facilitating localization of DNA
repair proteins and/or remodeling chromatin at DNA damage site during repair process

A mutation in the mouse Chd2 chromatin remodeler results in a complex renal phenotype (2008) Chd2 mutant created by gene trap in C-terminal end resulting in a truncated Chd2 mutant missing part of DNA-binding domain Homozygous Chd2 mutation resulted in perinatal lethality, while heterozygous mice developed multiple abnormalities, the most prevalent of which involved the kidneys Chd2-mutant mice present with glomerulopathy, proteinuria, and significantly impaired kidney function, as well as anemia Conclusions: Chd2 plays a major role in the maintenance of kidney function

Disruption of Chromodomain Helicase DNA Binding Protein 2 (CHD2) Causes Scoliosis (2008) Characterize a female patient with a chromosomal translocation in which a breakpoint at 15q26.1 disrupts Chd2 resulting in a phenotype of scoliosis, hirsutism, learning problems, and developmental delay These symptoms are similar to CHARGE syndrome in which Chd7 is altered Compare to Chd2 mutant mouse (truncated C-terminal). Chd2 expressed in heart, forebrain, extremities, facial and dorsal regions during specific times of embryonic development Mice displayed lordokyphosis, reduced body fat, postnatal runting, and growth retardation Conclusions: haploinsufficiency for CHD2 could result in a complex of abnormal human phenotypes that includes scoliosis and features similar to CHARGE syndrome

Mutation of the SNF2 Family Member Chd2 Affects Mouse Development and Survival (2006) Created original Chd2 gene trap missing C-terminal end (Chd2 exons 1-27 fused to geo)

Chd2 in mouse is ubiquitously expressed, vastly upregulated in heart Mutation resulted in general growth delay in homozygous mutants late in embryogenesis and in perinatal lethality In heterozygotes, noted decreased neonatal viability and increased susceptibility to nonneoplastic lesions affecting most primary organs. 85% showed gross kidney abnormalities Potential dominant negative effect: the mutant Chd2 protein might remain competent for proteinprotein interactions but is unable to stably interact with DNA, thereby sequestering factors that are needed for function away from the DNA Conclusions: Chd2 is important for continued organismal growth during perinatal development and postnatal survival, potentially playing a role in cell-cycle progression