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The Response of Histone H3.3 to Chromosomal Misalignment and Missegregation: a Novel Biochemical Pathway Correlated to Cell Cycle Arrest
Author(s) -
Fadness Sela,
Day Charles A.,
Langfald Alyssa,
Hinchcliffe Edward H.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.932.1
Subject(s) - anaphase , spindle checkpoint , mitosis , aneuploidy , kinetochore , chromosome segregation , microbiology and biotechnology , biology , chromosome instability , cell cycle , cancer research , genetics , chromosome , cell , gene
The spindle assembly checkpoint monitors proper chromosome alignment before cells can proceed into anaphase. Aneuploidy, a common feature of tumor cells, results from incorrect alignment and attachment of chromosomes passing through the spindle assembly checkpoint and generates missegregation. Missegregation is the gain or loss of chromosomes during mitosis and is caused by either defects in sister chromatid cohesion or kinetochore‐microtubule attachments. The mechanism of how cells monitor and prevent aneuploidy is not entirely understood. The goal of this work is to investigate chromosome misalignment and missegregation during anaphase in mitosis. Our results have led us to identify a biochemical pathway that directly monitors chromosome missegregation and induces cell cycle arrest in response to aneuploidy. Histone H3.3, a variant of canonical Histone H3.1, has five key amino acid substitutions whose mutations are correlated with multiple cancers. Two prevalent mutations in H3.3 cause K27M and G34R amino acid substitutions, both of which flank Ser31. Phosphorylation of Ser31 in H3.3 is required for proper segregation during anaphase in mitosis. This phosphorylation typically occurs at pericentromeric regions (Hake et al., 2005). Chromosomes that lag during anaphase accumulate Ser31 phosphorylation along their arms. This phosphorylation continues after anaphase in both the micronucleus and aneuploid daughter nuclei. In our work presented here, Chk1 kinase phosphorylates Ser31 and is followed by Repoman PP1ϒ dephosphorylation of Ser31. Monitoring H3.3 Ser31 phosphorylation will contribute to our understanding of how aneuploidy is normally monitored and suppressed and will lead to further understanding of chromosome missegregation steps.