DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites
Summary: P53 is a master transcriptional regulator and effector of the DNA damage response (DDR) that localizes to DNA damage sites, in part, via an interaction with PARP1. However, the mechanisms that regulate p53 abundance and activity at PARP1-decorated DNA damage sites remain undefined. The PARP...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-04-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004223005217 |
| _version_ | 1827972422231392256 |
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| author | Qingsheng Yan Jingyi Ding Sumbul Jawed Khan Lee N. Lawton Margaret A. Shipp |
| author_facet | Qingsheng Yan Jingyi Ding Sumbul Jawed Khan Lee N. Lawton Margaret A. Shipp |
| author_sort | Qingsheng Yan |
| collection | DOAJ |
| description | Summary: P53 is a master transcriptional regulator and effector of the DNA damage response (DDR) that localizes to DNA damage sites, in part, via an interaction with PARP1. However, the mechanisms that regulate p53 abundance and activity at PARP1-decorated DNA damage sites remain undefined. The PARP9 (BAL1) macrodomain-containing protein and its partner DTX3L (BBAP) E3 ligase are rapidly recruited to PARP1-PARylated DNA damage sites. During an initial DDR, we found that DTX3L rapidly colocalized with p53, polyubiquitylated its lysine-rich C-terminal domain, and targeted p53 for proteasomal degradation. DTX3L knockout significantly increased and prolonged p53 retention at PARP-decorated DNA damage sites. These findings reveal a non-redundant, PARP- and PARylation-dependent role for DTX3L in the spatiotemporal regulation of p53 during an initial DDR. Our studies suggest that targeted inhibition of DTX3L may augment the efficacy of certain DNA-damaging agents by increasing p53 abundance and activity. |
| first_indexed | 2024-04-09T19:21:57Z |
| format | Article |
| id | doaj.art-1a25c30a47ef4be387c3ab40b42f1601 |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-09T19:21:57Z |
| publishDate | 2023-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-1a25c30a47ef4be387c3ab40b42f16012023-04-05T08:30:09ZengElsevieriScience2589-00422023-04-01264106444DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sitesQingsheng Yan0Jingyi Ding1Sumbul Jawed Khan2Lee N. Lawton3Margaret A. Shipp4Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USADepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Corresponding authorSummary: P53 is a master transcriptional regulator and effector of the DNA damage response (DDR) that localizes to DNA damage sites, in part, via an interaction with PARP1. However, the mechanisms that regulate p53 abundance and activity at PARP1-decorated DNA damage sites remain undefined. The PARP9 (BAL1) macrodomain-containing protein and its partner DTX3L (BBAP) E3 ligase are rapidly recruited to PARP1-PARylated DNA damage sites. During an initial DDR, we found that DTX3L rapidly colocalized with p53, polyubiquitylated its lysine-rich C-terminal domain, and targeted p53 for proteasomal degradation. DTX3L knockout significantly increased and prolonged p53 retention at PARP-decorated DNA damage sites. These findings reveal a non-redundant, PARP- and PARylation-dependent role for DTX3L in the spatiotemporal regulation of p53 during an initial DDR. Our studies suggest that targeted inhibition of DTX3L may augment the efficacy of certain DNA-damaging agents by increasing p53 abundance and activity.http://www.sciencedirect.com/science/article/pii/S2589004223005217Biochemical mechanismCell biologyMolecular mechanism of gene regulation |
| spellingShingle | Qingsheng Yan Jingyi Ding Sumbul Jawed Khan Lee N. Lawton Margaret A. Shipp DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites iScience Biochemical mechanism Cell biology Molecular mechanism of gene regulation |
| title | DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites |
| title_full | DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites |
| title_fullStr | DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites |
| title_full_unstemmed | DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites |
| title_short | DTX3L E3 ligase targets p53 for degradation at poly ADP-ribose polymerase-associated DNA damage sites |
| title_sort | dtx3l e3 ligase targets p53 for degradation at poly adp ribose polymerase associated dna damage sites |
| topic | Biochemical mechanism Cell biology Molecular mechanism of gene regulation |
| url | http://www.sciencedirect.com/science/article/pii/S2589004223005217 |
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