Pirh2

Abstract

PerSPeCtive U biquitylation is currently recognized as a major posttranslational modification that regulates diverse cellular processes. Pirh2 is a ubiquitin E3 ligase that regulates the turnover and functionality of several proteins involved in cell proliferation and differentiation, cell cycle checkpoints, and cell death. Here we review the role of Pirh2 as a regulator of the DNA damage response through the ubiquitylation of p53, Chk2, p73, and PolH. By ubiquitylating these proteins, Pirh2 regulates cell cycle checkpoints and cell death in response to DNA double-strand breaks or the formation of bulky DNA lesions. We also discuss how Pirh2 affects cell proliferation and differentiation in unstressed conditions through ubiquitylation and degradation of c-Myc, p63, and p27 kip1 . Finally, we link these different functions of Pirh2 to its role as a tumor suppressor in mice and as a prognosis marker in various human cancer subtypes.

USP28 Is Recruited to Sites of DNA Damage by the Tandem BRCT Domains of 53BP1 but Plays a Minor Role in Double-Strand Break Metabolism

“…Furthermore, recent work identified the PIRH2 E3 ligase as a regulator of CHK2 stability and showed that USP28 can interact with PIRH2 and CHK2 in the context of USP28 overexpression (61). Interestingly, PIRH2 was also implicated in regulating c-Myc stability and the DDR (61)(62)(63). While again consistent with previous data suggesting that USP28 regulates CHK2, the functional relevance of this interaction for the DDR remains unclear, as we have found that Usp28 knockout animals do not recapitulate any of the predicted phenotypes, such as destabilized CHK2 or impaired IR-induced apoptosis.…”

Regulation of the p53 Family Proteins by the Ubiquitin Proteasomal Pathway

“…Pirh2, an E3 ligase that promotes the degradation of p53 (see above) can also target p63 and p73 for proteasomal degradation [235]. Pirh2 is able to ubiquitinate TAp63 and ∆Np63, which have been found to be vital for normal cell differentiation in the context of keratinocytes [218].…”

The Regulation of Tumor Suppressor p63 by the Ubiquitin-Proteasome System

“…Pirh2 (p53-induced protein with an RING-H2 domain) [96] is a RING-containing E-3 ligase able to bind to and target all members of the p53 family for degradation [97,98,99,100]. Pirh2 is able to induce degradation of both TAp63 and ΔNp63 isoforms [99], in cooperation with the E-2 enzyme UbcH5b [97].…”

“…Pirh2 can also induce degradation of p73 [99,101], and p21 [86]. It can be transactivated by p53, another example of a negative feedback loop and possible competition between family members [96]. …”