Journal
GENETICS
Volume 174, Issue 3, Pages 1115-1133Publisher
GENETICS SOCIETY AMERICA
DOI: 10.1534/genetics.105.051375
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Funding
- NCI NIH HHS [R01CA107300, R01 CA107300] Funding Source: Medline
- NHGRI NIH HHS [T32 HG002536] Funding Source: Medline
- NICHD NIH HHS [R01 HD041451, R01 HD41451:01] Funding Source: Medline
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The inactive X chromosome of female mammals displays several properties of heterochromatin including late replication, histone H4 hypoacetylation, historic H3 hypomethylation at lysine-4, and methylated CpG islands. We show that cre-Lox-mediated excision of 21 kb from both Xist alleles in female mouse fibroblasts led to the appearance of two historic modifications throughout the inactive X chromosome usually associated with euchromatin: historic H4 acetylation and histone H3 lysine-4 methylation. Despite these euchromatic properties, the inactive X chromosome was replicated even later in S phase than in wild-type female cells. Homozygosity for the deletion also caused regions of the active X chromosome that are associated with very high concentrations of LINE-1 elements to be replicated very late in S phase. Extreme late replication is a property of fragile sites and the 21-kb deletions destabilized the DNA of both X chromosomes, leading to deletions and translocations. This was accompanied by the phosphorylation of p53 at serine-15, an event that occurs in response to DNA damage, and the accumulation of gamma-H2AX, a histone involved in DNA repair, on the X chromosome. The Xist locus therefore maintains the DNA stability of both X chromosomes.
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