Modification of the base excision repair enzyme MBD4 by the small ubiquitin-like molecule SUMO1

Sannai, Mara; Doneddu, Valentina; Giri, Veda N.; Seeholzer, Steven H.; Nicolas, Émmanuelle; Yip, Shu-Chin; Bassi, Maria Rosaria; Mancuso, Pietro; Cortellino, Salvatore; Cigliano, Antonio; Lurie, Rebecca; Ding, Hua; Chernoff, Jonathan; Sobol, Robert W.; Yen, Timothy; Bagella, Luigi; Bellacosa, Alfonso

doi:10.1016/j.dnarep.2019.102687

Cited by 5 publications

(3 citation statements)

References 66 publications

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“…The G:T/U mismatch glycosylase MBD4 (methyl-CpG binding domain 4) is SUMOylated in response to DNA damage. In vitro, SUMO1-modified MBD4 has higher thymine glycosylase activity [ 27 ]. The scaffold protein XRCC1 (X-ray repair cross complementing 1) recruits BER repair factors including POLB (polymerase β), LIG3 (ligase 3) and PARP1 (poly (ADP-ribose) polymerase 1), which together replace the correct nucleotide and seal the nick in the DNA backbone.…”

Section: Base Excision Repair and Single Strand Break Repairmentioning

confidence: 99%

SUMO and the DNA damage response

Bhachoo,

Garvin

2024

Biochemical Society Transactions

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The preservation of genome integrity requires specialised DNA damage repair (DDR) signalling pathways to respond to each type of DNA damage. A key feature of DDR is the integration of numerous post-translational modification signals with DNA repair factors. These modifications influence DDR factor recruitment to damaged DNA, activity, protein-protein interactions, and ultimately eviction to enable access for subsequent repair factors or termination of DDR signalling. SUMO1-3 (small ubiquitin-like modifier 1-3) conjugation has gained much recent attention. The SUMO-modified proteome is enriched with DNA repair factors. Here we provide a snapshot of our current understanding of how SUMO signalling impacts the major DNA repair pathways in mammalian cells. We highlight repeating themes of SUMO signalling used throughout DNA repair pathways including the assembly of protein complexes, competition with ubiquitin to promote DDR factor stability and ubiquitin-dependent degradation or extraction of SUMOylated DDR factors. As SUMO ‘addiction’ in cancer cells is protective to genomic integrity, targeting components of the SUMO machinery to potentiate DNA damaging therapy or exacerbate existing DNA repair defects is a promising area of study.

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Section: Base Excision Repair and Single Strand Break Repairmentioning

confidence: 99%

SUMO and the DNA damage response

Bhachoo,

Garvin

2024

Biochemical Society Transactions

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“…MBD4 then recruits DNMT1 and promotes the remethylation of newly repaired CpG sites, ensuring the maintenance of the genomic methylation pattern [ 118 ]. Post-translational modifications of proteins involved in epigenetic regulation, such as ubiquitination and SUMOylation, can affect their function and impair epigenetic mechanisms [ 119 , 120 ] ( Figure 2 ).…”

Section: Epigenetics and Inflammationmentioning

confidence: 99%

The Killer’s Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer

Mecca,

Picerno,

Cortellino

2024

IJMS

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Inflammation is a key contributor to both the initiation and progression of tumors, and it can be triggered by genetic instability within tumors, as well as by lifestyle and dietary factors. The inflammatory response plays a critical role in the genetic and epigenetic reprogramming of tumor cells, as well as in the cells that comprise the tumor microenvironment. Cells in the microenvironment acquire a phenotype that promotes immune evasion, progression, and metastasis. We will review the mechanisms and pathways involved in the interaction between tumors, inflammation, and nutrition, the limitations of current therapies, and discuss potential future therapeutic approaches.

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“…MBD4 forms a complex with the DNA mismatch repair protein MLH1 and Fas-associated death domain protein (FADD), and these interactions are apparently required to promote mismatch repair-directed apoptosis initiated by certain types of DNA damage, e. g., extensive 5-fluorouracil incorporation [153,169,170]. 5-Fluorouracil as well as N-methyl-N-nitrosourea and cisplatin induce sumoylation of MBD4 at lysines 137, 215, and 377 in the interdomain linker, which stimulates the enzyme's activity [171]. Phosphorylation of the Ser165 and Ser262 in the interdomain linker by protein kinase C is also stimulatory [172].…”

Section: Methyl-binding Domainsmentioning

confidence: 99%

Noncatalytic Domains in DNA Glycosylases

Torgasheva

Diatlova

Grin

et al. 2022

IJMS

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Many proteins consist of two or more structural domains: separate parts that have a defined structure and function. For example, in enzymes, the catalytic activity is often localized in a core fragment, while other domains or disordered parts of the same protein participate in a number of regulatory processes. This situation is often observed in many DNA glycosylases, the proteins that remove damaged nucleobases thus initiating base excision DNA repair. This review covers the present knowledge about the functions and evolution of such noncatalytic parts in DNA glycosylases, mostly concerned with the human enzymes but also considering some unique members of this group coming from plants and prokaryotes.

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Modification of the base excision repair enzyme MBD4 by the small ubiquitin-like molecule SUMO1

Cited by 5 publications

References 66 publications

SUMO and the DNA damage response

SUMO and the DNA damage response

The Killer’s Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer

Noncatalytic Domains in DNA Glycosylases

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