Loss of ATRX leads to chromosome cohesion and congression defects

Abstract

αThalassemia/mental retardation X linked (ATRX) is a switch/sucrose nonfermenting-type ATPase localized at pericentromeric heterochromatin in mouse and human cells. Human ATRX mutations give rise to mental retardation syndromes characterized by developmental delay, facial dysmorphisms, cognitive deficits, and microcephaly and the loss of ATRX in the mouse brain leads to reduced cortical size. We find that ATRX is required for normal mitotic progression in human cultured cells and in neuroprogenitors. Using live cell imaging, we show that the transition from prometaphase to metaphase is prolonged in ATRX-depleted cells and is accompanied by defective sister chromatid cohesion and congression at the metaphase plate. We also demonstrate that loss of ATRX in the embryonic mouse brain induces mitotic defects in neuroprogenitors in vivo with evidence of abnormal chromosome congression and segregation. These findings reveal that ATRX contributes to chromosome dynamics during mitosis and provide a possible cellular explanation for reduced cortical size and abnormal brain development associated with ATRX deficiency.

Alpha Thalassemia/Mental Retardation Syndrome X-linked Gene Product ATRX Is Required for Proper Replication Restart and Cellular Resistance to Replication Stress

“…For example, in ATRX knockdown HeLa cells, a subset of meta-phase chromosomes failed to condense and the sister chromatids lacked centromeric cohesion, which coincided with spindle checkpoint activation in these cells (16). Presence of micronuclei following G1 entry was also observed in ATRX knockdown cells (16). These and other observations all indicate that ATRX deficiency may lead to genomic instability (11,16,(23)(24)(25).…”

“…ATRX Is Involved in Replication Stress-Because of the genomic instability reported in ATRX knockdown cells as well as in ATRX-deficient ALT cells (11,16), we speculated that ATRX may play a role in DNA damage response. To test this hypothesis, we treated wild-type and two independent clones of ATRX-deficient cells with different genotoxic agents.…”

“…Presence of micronuclei following G1 entry was also observed in ATRX knockdown cells (16). These and other observations all indicate that ATRX deficiency may lead to genomic instability (11,16,(23)(24)(25). However, it is unknown whether or not ATRX is directly involved in DNA damage response.…”

“…In addition, ATRX is implicated in mitotic and meiotic regulation. For example, in ATRX knockdown HeLa cells, a subset of meta-phase chromosomes failed to condense and the sister chromatids lacked centromeric cohesion, which coincided with spindle checkpoint activation in these cells (16). Presence of micronuclei following G1 entry was also observed in ATRX knockdown cells (16).…”

Cell cycle-specific cleavage of Scc2 regulates its cohesin deposition activity

“…Xenopus Scc2/Scc4 chromatin association requires prereplication complexes and Drf1-dependent kinase (DDK) activity (10,12,20), although this scenario is not the case in budding yeast (21). Scc2/Scc4 interactions with histone deacetylases and an ATP-dependent chromatin remodeler suggest that underlying chromatin structure also influences Scc2/Scc4 chromatin association (22)(23)(24)(25)(26). Whether Scc2/Scc4 plays a role in chromatin remodeling or merely deposits cohesins at remodeled sites is unknown, however.…”