ABSTRACT
The patient was a 55-year-old man who complained of lower abdominal pain and fever, and was admitted to an emergency clinic. His diagnosis was rectal perforation combined with intraperitoneal abscess. Because his condition was in the preseptic state, an emergency operation was performed for colostomy and abscess drainage. After operation, he was diagnosed with rectal cancer colonoscopically. He refused reoperation and selected an oral chemotherapy regimen (UFT+LV therapy). 18 months later, he underwent Hartmann's operation. Histologically, cancer cells were absent. Complete response to chemotherapy was confirmed. He is free from any sign of recurrence until now.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Leucovorin/therapeutic use , Rectal Neoplasms/drug therapy , Administration, Oral , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Colostomy , Combined Modality Therapy , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Rectal Neoplasms/pathology , Rectal Neoplasms/surgery , Remission Induction , Tegafur/administration & dosage , Tegafur/therapeutic use , Tomography, X-Ray Computed , Uracil/administration & dosage , Uracil/therapeutic useABSTRACT
The breast and ovarian tumor suppressor BRCA1 catalyzes untraditional polyubiquitin chains that could be a signal for processes other than proteolysis. However, despite intense investigations, the mechanisms regulated by the enzyme activity remain only partially understood. Here, we report that BRCA1-BARD1 mediates polyubiquitination of RPB8, a common subunit of RNA polymerases, in response to DNA damage. A proteomics screen identified RPB8 as a protein modified after epirubicin treatment in BRCA1-dependent manner. RPB8 interacted with BRCA1-BARD1 and was polyubiquitinated by BRCA1-BARD1 in vivo and in vitro. BRCA1-BARD1 did not destabilize RPB8 in vivo but rather caused an increase in the amount of soluble RPB8. Importantly, RPB8 was polyubiquitinated immediately after UV irradiation in a manner sensitive to BRCA1 knockdown by RNA interference. Substitution of five lysine residues of RPB8 with arginine residues abolished its ability to be ubiquitinated while preserving its polymerase activity. HeLa cell lines stably expressing this ubiquitin-resistant form of RPB8 exhibited UV hypersensitivity accompanied by up-regulated caspase activity. Our findings suggest that ubiquitination of a common subunit of RNA polymerases is a mechanism underlying BRCA1-dependent cell survival after DNA damage.
