<i>BRCA1</i>promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Tian, Fen; Sharma, Shilpy; Zou, Jianqiu; Lin, Shiaw Yih; Wang, Bin; Rezvani, Khosrow; Wang, Hongmin; Parvin, Jeffrey D.; Ludwig, Thomas; Canman, Christine E.; Zhang, Dong

doi:10.1073/pnas.1306534110

Cited by 45 publications

(50 citation statements)

References 39 publications

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“…A key event in regulation of TLS is the monoubiquitination of PCNA (34,37,53,54). PCNA is monoubiquitinated in response to DNA damage induced by UV or other chemical reagents, such as mitomycin C (MMC), hydroxyurea (HU), methyl methanesulfonate (MMS), and aphidicolin (55)(56)(57). We found that monoubiquitination of PCNA in response to UV treatment is enhanced in the presence of LANA.…”

Section: Discussionmentioning

confidence: 94%

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Sun

Jha

Robertson

2015

J Virol

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Latent DNA replication of Kaposi's sarcoma-associated herpesvirus (KSHV) initiates at the terminal repeat (TR) element and requires trans-acting elements, both viral and cellular, such as ORCs, MCMs, and latency-associated nuclear antigen (LANA). However, how cellular proteins are recruited to the viral genome is not very clear. Here, we demonstrated that the host cellular protein, Bub1, is involved in KSHV latent DNA replication. We show that Bub1 constitutively interacts with proliferating cell nuclear antigen (PCNA) via a highly conserved PIP box motif within the kinase domain. Furthermore, we demonstrated that Bub1 can form a complex with LANA and PCNA in KSHV-positive cells. This strongly indicated that Bub1 serves as a scaffold or molecular bridge between LANA and PCNA. LANA recruited PCNA to the KSHV genome via Bub1 to initiate viral replication in S phase and interacted with PCNA to promote its monoubiquitination in response to UV-induced damage for translesion DNA synthesis. This resulted in increased survival of KSHV-infected cells. IMPORTANCEDuring latency in KSHV-infected cells, the viral episomal DNA replicates once each cell cycle. KSHV does not express DNA replication proteins during latency. Instead, KSHV LANA recruits the host cell DNA replication machinery to the replication origin. However, the mechanism by which LANA mediates replication is uncertain. Here, we show that LANA is able to form a complex with PCNA, a critical protein for viral DNA replication. Furthermore, our findings suggest that Bub1, a spindle checkpoint protein, serves as a scaffold or molecular bridge between LANA and PCNA. Our data further support a role for Bub1 and LANA in PCNA-mediated cellular DNA replication processes as well as monoubiquitination of PCNA in response to UV damage. These data reveal a therapeutic target for inhibition of KSHV persistence in malignant cells. K aposi's sarcoma-associated herpesvirus (KSHV) or human herpesvirus 8, an oncogenic member of the gammaherpesvirus subfamily, was first identified in 1994 from body cavity-based lymphoma (BCBL) and HIV-infected patients with Kaposi's sarcoma (KS) (1). KSHV is believed to be the etiological agent of several human cancers, including KS (1, 2), primary effusion lymphoma (PEL) or body cavity based lymphoma (3), and multicentric Castleman's disease (MCD) (4, 5). Additionally, there have been reports of KSHV-associated solid lymphomas in HIV-positive and -negative patients as well as KSHV-associated lymphomas in patients with primary immune deficiencies, such as common variable immune deficiency (6, 7). Similar to other members of the gammaherpesvirus family, KSHV establishes a predominantly latent infection in host cells after primary infection (8). During latent infections, the KSHV genome persists as a circular doublestranded DNA (episome) with most viral genes being silenced, except for a small number of latent genes, which include the viral cyclin (v-cyclin), the latency-associated nuclear antigen (LANA), and the viral FLICE inhibitory prote...

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Section: Discussionmentioning

confidence: 94%

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Sun

Jha

Robertson

2015

J Virol

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“…We speculate that the damage induced phosphorylation of BRCA1 may be involved. 43 Both BRCA1 and FancJ have well-established roles in DNA damage checkpoint and DNA repair which take place early during DDR. DDICA occurs much later (often a few days later).…”

Section: Discussionmentioning

confidence: 99%

“…[18][19][20] We recently showed that prolonged treatment of 2 ICLs, MMC and cis-platin, also induces pronounced centrosome amplification, 38 suggesting that the induction of centrosome amplification is likely an integral part of DDR. Because BRCA1 is such an important DDR protein and is modified and stabilized during sustained DNA damage, 26,27,43 we then investigated whether BRCA1 is also involved in DDICA. Interestingly, depletion of BRCA1 reduced the MMC-and HU-induced centrosome amplification by about 30-50% ( Fig.…”

Section: Brca1 Promotes Dna Damage-induced Centrosome Amplificationmentioning

confidence: 99%

BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1

et al. 2014

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DNA damage response (DDR) and the centrosome cycle are 2 of the most critical cellular processes affecting the genome stability in animal cells. Yet the cross-talks between DDR and the centrosome are poorly understood. Here we showed that deficiency of the breast cancer 1, early onset gene (BRCA1) induces centrosome amplification in nonstressed cells as previously reported while attenuating DNA damage-induced centrosome amplification (DDICA) in cells experiencing prolonged genotoxic stress. Mechanistically, the function of BRCA1 in promoting DDICA is through binding and recruiting polo-like kinase 1 (PLK1) to the centrosome. In a recent study, we showed that FancJ also suppresses centrosome amplification in non-stressed cells while promoting DDICA in both hydroxyurea and mitomycin C treated cells. FancJ is a key component of the BRCA1 B-complex. Here, we further demonstrated that, in coordination with BRCA1, FancJ promotes DDICA by recruiting both BRCA1 and PLK1 to the centrosome in the DNA damaged cells. Thus, we have uncovered a novel role of BRCA1 and FancJ in the regulation of DDICA. Dysregulation of DDR or centrosome cycle leads to aneuploidy, which is frequently seen in both solid and hematological cancers. BRCA1 and FancJ are known tumor suppressors and have well-recognized functions in DNA damage checkpoint and DNA repair. Together with our recent findings, we demonstrated here that BRCA1 and FancJ also play an important role in centrosome cycle especially in DDICA. DDICA is thought to be an alternative fail-safe mechanism to prevent cells experiencing severe DNA damage from becoming carcinogenic. Therefore, BRCA1 and FancJ are potential liaisons linking early DDR with the DDICA. We propose that together with their functions in DDR, the role of BRCA1 and FancJ in the activation of DDICA is also crucial for their tumor suppression functions in vivo.

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“…In addition to the major E3 ubiquitin ligase RAD18, several other E3 ligases, like RNF8 (Zhang et al, 2008) and CRL cdt2 (Terai et al, 2010), have been reported to regulate PCNA-mUb. Additionally, many factors, including apoptosis regulatory protein Siva (SIVA1) (Han et al, 2014), Spartan/C1orf124 [ protein with sprT-like domain at the N-terminus, also known as DNA damage protein targeting VCP (DVC1)] (Centore et al, 2012), MutS protein homolog 2 (MSH2) (Zlatanou et al, 2011;Lv et al, 2013), breast cancer 1 (BRCA1) (Tian et al, 2013), have also been found to regulate the RAD18-dependent PCNA-mUb. Ubiquitin-specific protease 1 (USP1) also participates in the regulation of PCNA-mUb as a key deubiquitylase (DUB) for deubiquitylating PCNA-mUb (Huang et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

REV1 promotes PCNA monoubiquitylation through interacting with ubiquitylated RAD18

Wang

Huang

et al. 2016

Journal of Cell Science

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Translesion DNA synthesis (TLS) is a mode of DNA damage tolerance which plays an important role in genome mutagenesis and chromatin integrity maintenance. Proliferating cell nuclear antigen (PCNA) monoubiquitylation is one of the key factors for TLS pathway choice. So far, it remains unclear how the TLS pathway is elaborately regulated. Here, we report that TLS polymerase REV1 can promote PCNA monoubiquitylation after UV radiation. Further studies revealed that this stimulatory effect is mediated through the enhanced interaction between REV1 and ubiquitylated RAD18, which facilitates the release of nonubiquitylated RAD18 from ubiquitylated RAD18 trapping, after which RAD18 is recruited to chromatin for its TLS function. Furthermore, we found that this stimulatory effect could also be detected after exposure to hydroxyurea or mitomycin C, but not methyl methanesulfonate (MMS), which is in line with the fact that ubiquitylated RAD18 could not be detected after exposure to MMS.

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BRCA1promotes the ubiquitination of PCNA and recruitment of translesion polymerases in response to replication blockade

Cited by 45 publications

References 39 publications

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

Bub1 in Complex with LANA Recruits PCNA To Regulate Kaposi's Sarcoma-Associated Herpesvirus Latent Replication and DNA Translesion Synthesis

BRCA1 and FancJ cooperatively promote interstrand crosslinker induced centrosome amplification through the activation of polo-like kinase 1

REV1 promotes PCNA monoubiquitylation through interacting with ubiquitylated RAD18

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