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How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway.

Coleman KE, Huang TT - Front Genet (2016)

Bottom Line: Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs).SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood.Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York NY, USA.

ABSTRACT
Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs). ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination, nucleotide excision repair and translesion synthesis (TLS). SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

No MeSH data available.


Related in: MedlinePlus

Control of the FA pathway by SUMO and SUMO-like modifications. (A) Regulated release of the FAAP20 subunit from FANCA is required for SUMOylation of FANCA via the E2 conjugating enzyme Ubc9. Removal of FAAP20 inhibits the recruitment of the downstream TLS polymerase REV1 during ICL repair, resulting in decreased TLS-mediated mutagenesis. SUMOylation of FANCA subsequently triggers RNF4-mediated polyubiquitylation and proteasome-mediated degradation. (B) The ID complex is targeted for SUMOylation in a manner dependent on the activities of the ATR kinase, the FA core complex, and the SUMO E3 ligases PIAS1/PIAS4. Alternatively, SUMOylation can be removed by the SUMO protease SENP6. SUMOylation of the ID complex allows for recognition by RNF4, leading to ID complex polyubiquitylation and removal from damage sites via the DVC1-p97 segregase complex. (C) The SLX4 complex acts as a SUMO E3 ligase by triggering its own SUMOylation in addition to that of the DNA repair/recombination endonuclease XPF. This SLX4-dependent SUMOylation is dependent on the E2 Ubc9, as well as its own SIMs and BTB domains, and is important to prevent mitotic catastrophe following CFS expression. (D) The SUMO E3 ligases PIAS1 and PIAS4 promote DSB repair by localizing to damage sites and SUMOylating multiple target proteins, including BRCA1 and 53BP1. This SUMOylation is required for proper ubiquitin-adduct formation mediated by RNF8, RNF168, and BRCA1 to initiate a DNA damage response (DDR). (E) The SUMO-like domain SLD2 of UAF1 directs USP1-UAF1 targeting to its substrates via SIMs located within FANCI and the PCNA-interacting protein hELG1. These SLD-SIM interactions regulate deubiquitylation of FANCD2 and PCNA-Ub substrates, respectively, to coordinate HR and TLS activities during FA DNA repair.
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Figure 2: Control of the FA pathway by SUMO and SUMO-like modifications. (A) Regulated release of the FAAP20 subunit from FANCA is required for SUMOylation of FANCA via the E2 conjugating enzyme Ubc9. Removal of FAAP20 inhibits the recruitment of the downstream TLS polymerase REV1 during ICL repair, resulting in decreased TLS-mediated mutagenesis. SUMOylation of FANCA subsequently triggers RNF4-mediated polyubiquitylation and proteasome-mediated degradation. (B) The ID complex is targeted for SUMOylation in a manner dependent on the activities of the ATR kinase, the FA core complex, and the SUMO E3 ligases PIAS1/PIAS4. Alternatively, SUMOylation can be removed by the SUMO protease SENP6. SUMOylation of the ID complex allows for recognition by RNF4, leading to ID complex polyubiquitylation and removal from damage sites via the DVC1-p97 segregase complex. (C) The SLX4 complex acts as a SUMO E3 ligase by triggering its own SUMOylation in addition to that of the DNA repair/recombination endonuclease XPF. This SLX4-dependent SUMOylation is dependent on the E2 Ubc9, as well as its own SIMs and BTB domains, and is important to prevent mitotic catastrophe following CFS expression. (D) The SUMO E3 ligases PIAS1 and PIAS4 promote DSB repair by localizing to damage sites and SUMOylating multiple target proteins, including BRCA1 and 53BP1. This SUMOylation is required for proper ubiquitin-adduct formation mediated by RNF8, RNF168, and BRCA1 to initiate a DNA damage response (DDR). (E) The SUMO-like domain SLD2 of UAF1 directs USP1-UAF1 targeting to its substrates via SIMs located within FANCI and the PCNA-interacting protein hELG1. These SLD-SIM interactions regulate deubiquitylation of FANCD2 and PCNA-Ub substrates, respectively, to coordinate HR and TLS activities during FA DNA repair.

Mentions: One example of how SUMOylation contributes to FA pathway regulation is through promoting the polyubiquitylation of FA core complex member FANCA. A recent study from the D’Andrea lab identified a patient with a point mutation in FANCA (FANCAI935S) that fails to bind the FAAP20 subunit of the FA core complex, leading to decreased FANCA protein levels. In uncovering the mechanism behind this decreased stability of FANCA, the authors discovered that defective FAAP20 binding by the FANCA mutant leads to increased exposure of a SUMOylation site on FANCA at residue K921, which in turn promotes UBC9-mediated SUMOylation, polyubiquitylation by the STUbL RNF4, and proteasome-dependent degradation of FANCA. Failure of the FANCA mutant to bind FAAP20 still allows efficient FANCD2 monoubiquitylation, but leads to an inability to properly recruit the REV1 translesion polymerase (Kim et al., 2012), contributing to lower rates of TLS-mediated mutagenesis. On the other hand, the authors showed that wild-type FANCA is also subject to SUMOylation and RNF4-mediated polyubiquitylation, but to a lesser degree, and depletion of RNF4 contributed to increased MMC sensitivity (Xie et al., 2015) (Figure 2A). Taken together, these results indicate that the regulated release of FAAP20 from FANCA is a normal critical step in the FA pathway and suggest that failure to properly release FANCA from the FA core complex could contribute to pathway disruption and genome instability.


How SUMOylation Fine-Tunes the Fanconi Anemia DNA Repair Pathway.

Coleman KE, Huang TT - Front Genet (2016)

Control of the FA pathway by SUMO and SUMO-like modifications. (A) Regulated release of the FAAP20 subunit from FANCA is required for SUMOylation of FANCA via the E2 conjugating enzyme Ubc9. Removal of FAAP20 inhibits the recruitment of the downstream TLS polymerase REV1 during ICL repair, resulting in decreased TLS-mediated mutagenesis. SUMOylation of FANCA subsequently triggers RNF4-mediated polyubiquitylation and proteasome-mediated degradation. (B) The ID complex is targeted for SUMOylation in a manner dependent on the activities of the ATR kinase, the FA core complex, and the SUMO E3 ligases PIAS1/PIAS4. Alternatively, SUMOylation can be removed by the SUMO protease SENP6. SUMOylation of the ID complex allows for recognition by RNF4, leading to ID complex polyubiquitylation and removal from damage sites via the DVC1-p97 segregase complex. (C) The SLX4 complex acts as a SUMO E3 ligase by triggering its own SUMOylation in addition to that of the DNA repair/recombination endonuclease XPF. This SLX4-dependent SUMOylation is dependent on the E2 Ubc9, as well as its own SIMs and BTB domains, and is important to prevent mitotic catastrophe following CFS expression. (D) The SUMO E3 ligases PIAS1 and PIAS4 promote DSB repair by localizing to damage sites and SUMOylating multiple target proteins, including BRCA1 and 53BP1. This SUMOylation is required for proper ubiquitin-adduct formation mediated by RNF8, RNF168, and BRCA1 to initiate a DNA damage response (DDR). (E) The SUMO-like domain SLD2 of UAF1 directs USP1-UAF1 targeting to its substrates via SIMs located within FANCI and the PCNA-interacting protein hELG1. These SLD-SIM interactions regulate deubiquitylation of FANCD2 and PCNA-Ub substrates, respectively, to coordinate HR and TLS activities during FA DNA repair.
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Figure 2: Control of the FA pathway by SUMO and SUMO-like modifications. (A) Regulated release of the FAAP20 subunit from FANCA is required for SUMOylation of FANCA via the E2 conjugating enzyme Ubc9. Removal of FAAP20 inhibits the recruitment of the downstream TLS polymerase REV1 during ICL repair, resulting in decreased TLS-mediated mutagenesis. SUMOylation of FANCA subsequently triggers RNF4-mediated polyubiquitylation and proteasome-mediated degradation. (B) The ID complex is targeted for SUMOylation in a manner dependent on the activities of the ATR kinase, the FA core complex, and the SUMO E3 ligases PIAS1/PIAS4. Alternatively, SUMOylation can be removed by the SUMO protease SENP6. SUMOylation of the ID complex allows for recognition by RNF4, leading to ID complex polyubiquitylation and removal from damage sites via the DVC1-p97 segregase complex. (C) The SLX4 complex acts as a SUMO E3 ligase by triggering its own SUMOylation in addition to that of the DNA repair/recombination endonuclease XPF. This SLX4-dependent SUMOylation is dependent on the E2 Ubc9, as well as its own SIMs and BTB domains, and is important to prevent mitotic catastrophe following CFS expression. (D) The SUMO E3 ligases PIAS1 and PIAS4 promote DSB repair by localizing to damage sites and SUMOylating multiple target proteins, including BRCA1 and 53BP1. This SUMOylation is required for proper ubiquitin-adduct formation mediated by RNF8, RNF168, and BRCA1 to initiate a DNA damage response (DDR). (E) The SUMO-like domain SLD2 of UAF1 directs USP1-UAF1 targeting to its substrates via SIMs located within FANCI and the PCNA-interacting protein hELG1. These SLD-SIM interactions regulate deubiquitylation of FANCD2 and PCNA-Ub substrates, respectively, to coordinate HR and TLS activities during FA DNA repair.
Mentions: One example of how SUMOylation contributes to FA pathway regulation is through promoting the polyubiquitylation of FA core complex member FANCA. A recent study from the D’Andrea lab identified a patient with a point mutation in FANCA (FANCAI935S) that fails to bind the FAAP20 subunit of the FA core complex, leading to decreased FANCA protein levels. In uncovering the mechanism behind this decreased stability of FANCA, the authors discovered that defective FAAP20 binding by the FANCA mutant leads to increased exposure of a SUMOylation site on FANCA at residue K921, which in turn promotes UBC9-mediated SUMOylation, polyubiquitylation by the STUbL RNF4, and proteasome-dependent degradation of FANCA. Failure of the FANCA mutant to bind FAAP20 still allows efficient FANCD2 monoubiquitylation, but leads to an inability to properly recruit the REV1 translesion polymerase (Kim et al., 2012), contributing to lower rates of TLS-mediated mutagenesis. On the other hand, the authors showed that wild-type FANCA is also subject to SUMOylation and RNF4-mediated polyubiquitylation, but to a lesser degree, and depletion of RNF4 contributed to increased MMC sensitivity (Xie et al., 2015) (Figure 2A). Taken together, these results indicate that the regulated release of FAAP20 from FANCA is a normal critical step in the FA pathway and suggest that failure to properly release FANCA from the FA core complex could contribute to pathway disruption and genome instability.

Bottom Line: Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs).SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood.Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York NY, USA.

ABSTRACT
Fanconi anemia (FA) is a rare human genetic disorder characterized by developmental defects, bone marrow failure and cancer predisposition, primarily due to a deficiency in the repair of DNA interstrand crosslinks (ICLs). ICL repair through the FA DNA repair pathway is a complicated multi-step process, involving at least 19 FANC proteins and coordination of multiple DNA repair activities, including homologous recombination, nucleotide excision repair and translesion synthesis (TLS). SUMOylation is a critical regulator of several DNA repair pathways, however, the role of this modification in controlling the FA pathway is poorly understood. Here, we summarize recent advances in the fine-tuning of the FA pathway by small ubiquitin-like modifier (SUMO)-targeted ubiquitin ligases (STUbLs) and other SUMO-related interactions, and discuss the implications of these findings in the design of novel therapeutics for alleviating FA-associated condition, including cancer.

No MeSH data available.


Related in: MedlinePlus