PCNA Unloading Is Negatively Regulated by BET Proteins

• Published in: Cell reports (Cambridge) Vol. 29; no. 13; pp. 4632 - 4645.e5
• Main Authors: Kang, Mi-Sun, Kim, Jinwoo, Ryu, Eunjin, Ha, Na Young, Hwang, Sunyoung, Kim, Byung-Gyu, Ra, Jae Sun, Kim, Yeong Jae, Hwang, Jung Me, Myung, Kyungjae, Kang, Sukhyun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 24.12.2019; Elsevier
• Subjects: ATAD5; BET protein; BRD4; DNA replication; histone acetylation; nascent chromatin; PCNA; PCNA unloading; RFC-like complex; DNA replication; PCNA; ATAD5; BET protein; nascent chromatin; PCNA unloading; histone acetylation; BRD4; RFC-like complex
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.11.114

Proliferating cell nuclear antigen (PCNA) is a DNA clamp essential for DNA replication. During DNA synthesis, PCNA is continuously loaded onto and unloaded from DNA. PCNA recruits various proteins to nascent DNA to facilitate chromosome duplication. Therefore, timely PCNA unloading is crucial for high-fidelity DNA replication. The ATAD5-RFC-like complex (ATAD5-RLC) unloads PCNA from replicated DNA. It is unclear how ATAD5-RLC activity is regulated to prevent premature PCNA unloading. Here, we find that BRD4, an acetyl-histone-binding chromatin reader, inhibits the PCNA-unloading activity of ATAD5-RLC. The BRD4 ET domain interacts with a region upstream of the ATAD5 PCNA-unloading domain. BRD4-ATAD5 binds to acetyl-histones in nascent chromatin. BRD4 release from chromatin correlates with PCNA unloading. Disruption of the interaction between BRD4 and acetyl-histones or between BRD4 and ATAD5 reduces the PCNA amount on chromatin. In contrast, the overexpression of BRD4 increases the amount of chromatin-bound PCNA. Thus, acetyl-histone-bound BRD4 fine-tunes PCNA unloading from nascent DNA. [Display omitted] •ATAD5 and BRD4 are enriched on nascent DNA•A conserved region upstream of ATAD5 PCNA-unloading domain binds to BRD4 ET domain•Acetyl-histone-bound BRD4 inhibits PCNA unloading by ATAD5-RLC on nascent DNA Kang et al. demonstrate how PCNA unloading is regulated on nascent chromatin. Timely PCNA unloading from replicated DNA is crucial for faithful DNA replication. BRD4 binds to ATAD5, a subunit of PCNA-unloading complex. Acetyl-histone-bound BRD4 inhibits the activity of ATAD5 complex on nascent chromatin to prevent premature PCNA unloading.