HUWE1 (also known as HECT, UBA and WWE domain-containing protein 1, or Mcl-1 ubiquitin ligase E3, amongst other names) may function as a ubiquitin-protein ligase involved in the ubiquitination cascade that targets specific substrate proteins in proteolysis. It can ubiquitylate DNA polymerase beta (Pol beta), the major BER DNA polymerase, and modulates base excision repair (BER) []. HUWE1 also acts as a critical mediator of both the p53-independent and p53-dependent tumor suppressor functions of ARF tumor suppressor in p53 regulation []. Moreover, HUWE1 is both required and sufficient for the polyubiquitination of Mcl-1, an anti-apoptotic Bcl-2 family member involved in DNA damage-induced apoptosis []. Furthermore, HUWE1 plays an important role in the regulation of Cdc6 stability after DNA damage. In addition, HUWE1 works as a partner of N-Myc oncoprotein in neural cells. It ubiquitinates N-Myc and primes it for proteasomal-mediated degradation [].HUWE1 contains a ubiquitin-associated (UBA) domain, a WWE domain, and a Bcl-2 homology region 3 (BH3) domain at the N terminus and a HECT domain at the C terminus. WWE domain plays a role in the regulation of specific protein-protein interactions in a ubiquitin conjugation system. BH3 domain is responsible for the specific binding to Mcl-1. HECT domain is involved in the inhibition of the transcriptional activity of p53 via a ubiquitin-dependent degradation pathway [].
This entry represents the Telomere attrition and p53 response 1 protein (TAPR1) from animals, including TAPR1 (also known as C16orf72/HAPSTR1) from human, which functions as a negative regulator of TP53/P53 in the cellular response to telomere erosion and probably also DNA damage. It may attenuate p53/TP53 activation through the E3 ubiquitin ligase HUWE1 [, ].
This entry represents the Telomere attrition and p53 response 1 protein (TAPR1) from eukaryotes, including TAPR1 (also known as C16orf72/HAPSTR1) from human, which is a key multistress-responsive protein that functions as a negative regulator of TP53/P53 in the cellular response to telomere erosion and probably also DNA damage. It functions in cooperation with the E3 ubiquitin ligase HUWE1 which also promotes TAPR1's degradation [, ]. This family also includes the uncharacterised proteins from fungi, such as YJR056C from yeast.
This domain contains repetitive element (RE) from a subgroup of HECT E3 ubiquitin ligases and the Y-family translesion polymerases, including human HUWE1 and REV1. Each of these repetitive elements are approximately 20 amino acids in length and contain two predicted helical segments separated by a Leu-Pro motif. The REs from the Y-family polymerases were shown to bind ubiquitin and were the basis for a novel ubiquitin-binding domain called the ubiquitin-binding motif (UBM) [].
