Involvement of Histone 2 in Apoptosis Induced by dna double-Strand Breaks rcc1 (inxs/Bj1)

Involvement of Histone H1.2 in Apoptosis Induced by DNA Double-Strand Breaks

RCC1 (inxs/Bj1)

• Regulator of Chromatin Condensation-1:

• Regulates chromatin condensation prior to entry into mitosis (normally inhibits condensation until replication is complete; in mutants, get premature chromatin condensation (PCC) before the completion of DNA replication)

• Ran Guanine Nucleotide Exchange Factor (Ran GEF) required for Nuclear import (NLS proteins) and export (?)

• Mammalian RCC1 binds histones H2A and H2B (Ref: ____)

• Drosophila dRCC1 “associated with” nucleosomes (Frasch, 1991)

Major Histone Proteins

Nucleosome core particle

Organization of chromatin in nucleosomes

DNA damage-induced apoptosis

Question: What are the mechanisms of signal transmission from the nucleus to the mitochondria during DNA damage-induced apoptosis?

Purification of an X-ray-induced CytoC-Releasing Factor

The cytoC-releasing factor is Histone H1.2

Histone H1.2 induces cytoC release from isolated mitochondria

Histone H1.2 Cyto-C release is Bak-dependent

Histone H1.2 accumulates in the cytoplasm

Cytolasmic Histone H1.2 accumulation is p53-dependent

Histone H1.2 is released from the nucleus

Reduced Histone H1.2 expression inhibits X-ray-induced apoptosis

H1.2 is specific for DNA double-strand breaks

H1.2-Deficient mice are resistant to apoptosis induced by X-ray & etoposide

Discussion

• DNA double-strand breaks, but probably not UV damage, trigger a megabase range of chromatin remodeling which leads to release of a significant amount of H1 from the chromatin

• The amount of histone H1.2 released from the chromatin might be used for monitoring the extent of DNA damage

• The release of nuclear histone H1 and its accumulation in the cytoplasm suggest that nuclear import/export machinery must be affected by X-ray irradiation (look at role of inxs in X-ray induced apoptosis also??)

• How does H1.2 induce cytochrome C release?

• The major difference between H1.2 and the other H1s is at the C-terminal region: KXXKP exists in all H1s except H1.2 (negative regulatory sequence?)

Caspase-dependent deubiquitination of monoubiquitinated nucleosomal histone H2A induced by diverse apoptogenic stimuli

• Caspase-dependent deubiquitination of monoubiquitinated nucleosomal histone H2A induced by diverse apoptogenic stimuli

• Mimnaugh et al., CDD, 2001.

Transcriptional regulation & histone acetylation