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UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells

An, JY and Kim, E and Zakrzewska, A and Yoo, YD and Jang, JM and Han, DH and Lee, MJ and Seo, JW and Lee, YJ and Kim, TY and de Rooij, DG and Kim, BY and Kwon, YT (2012) UBR2 of the N-end rule pathway is required for chromosome stability via histone ubiquitylation in spermatocytes and somatic cells. PLoS ONE, 7 (5).

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Abstract

The N-end rule pathway is a proteolytic system in which its recognition components (N-recognins) recognize destabilizing N-terminal residues of short-lived proteins as an essential element of specific degrons, called N-degrons. The RING E3 ligases UBR2 and UBR1 are major N-recognins that share size (200 kDa), conserved domains and substrate specificities to N-degrons. Despite the known function of the N-end rule pathway in degradation of cytosolic proteins, the major phenotype of UBR2-deficient male mice is infertility caused by arrest of spermatocytes at meiotic prophase I. UBR2-deficient spermatocytes are impaired in transcriptional silencing of sex chromosome-linked genes and ubiquitylation of histone H2A. In this study we show that the recruitment of UBR2 to meiotic chromosomes spatiotemporally correlates to the induction of chromatin-associated ubiquitylation, which is significantly impaired in UBR2-deficient spermatocytes. UBR2 functions as a scaffold E3 that promotes HR6B/UbcH2-dependent ubiquitylation of H2A and H2B but not H3 and H4, through a mechanism distinct from typical polyubiquitylation. The E3 activity of UBR2 in histone ubiquitylation is allosterically activated by dipeptides bearing destabilizing N-terminal residues. Insufficient monoubiquitylation and polyubiquitylation on UBR2-deficient meiotic chromosomes correlate to defects in double strand break (DSB) repair and other meiotic processes, resulting in pachytene arrest at stage IV and apoptosis. Some of these functions of UBR2 are observed in somatic cells, in which UBR2 is a chromatin-binding protein involved in chromatin-associated ubiquitylation upon DNA damage. UBR2-deficient somatic cells show an array of chromosomal abnormalities, including hyperproliferation, chromosome instability, and hypersensitivity to DNA damage-inducing reagents. UBR2-deficient mice enriched in C57 background die upon birth with defects in lung expansion and neural development. Thus, UBR2, known as the recognition component of a major cellular proteolytic system, is associated with chromatin and controls chromatin dynamics and gene expression in both germ cells and somatic cells. © 2012 Kwon et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
An, JY
Kim, E
Zakrzewska, A
Yoo, YD
Jang, JM
Han, DH
Lee, MJ
Seo, JW
Lee, YJyjl2@pitt.eduYJL2
Kim, TY
de Rooij, DG
Kim, BY
Kwon, YTyok5@pitt.eduYOK5
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorDrevet, Joel R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 17 May 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 5
DOI or Unique Handle: 10.1371/journal.pone.0037414
Schools and Programs: School of Medicine > Surgery
School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
MeSH Headings: Animals; Animals, Newborn; Chromatin--metabolism; Chromosomal Instability--physiology; DNA Repair--physiology; Fibroblasts--metabolism; Histones--metabolism; Humans; Male; Meiosis; Mice; Pachytene Stage--drug effects; Pulmonary Alveoli--abnormalities; Spermatocytes--metabolism; Ubiquitin-Protein Ligases--deficiency; Ubiquitin-Protein Ligases--metabolism; Ubiquitin-Protein Ligases--physiology; Ubiquitination
Other ID: NLM PMC3355131
PubMed Central ID: PMC3355131
PubMed ID: 22616001
Date Deposited: 04 Oct 2012 14:16
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/15570

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