Mind the gap: Keeping UV lesions in check

Novarina, Daniele; Amara, Flavio; Lazzaro, Federico; Plevani, Paolo; Muzi-Falconi, Marco

doi:10.1016/j.dnarep.2011.04.030

Cited by 38 publications

(34 citation statements)

References 103 publications

(92 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We therefore examined the formation of CPDs, the most abundant UV light-induced DNA lesion. CPDs are formed by the covalent linkage of the ring carbon 5 (C5) and C6 bonds of adjacent pyrimidines (37). Immediately after UVC exposure, CPD formation was significantly higher in fibroblasts from AGS and SLE patients compared with WT fibroblasts ( Figure 6A).…”

Section: Carriers Of Ags Mutations Frequently Develop Sle-associated mentioning

confidence: 99%

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Günther¹,

Kind²,

Reijns³

et al. 2014

J. Clin. Invest.

196

178

View full text Add to dashboard Cite

Genome integrity is continuously challenged by the DNA damage that arises during normal cell metabolism. Biallelic mutations in the genes encoding the genome surveillance enzyme ribonuclease H2 (RNase H2) cause Aicardi-Goutières syndrome (AGS), a pediatric disorder that shares features with the autoimmune disease systemic lupus erythematosus (SLE). Here we determined that heterozygous parents of AGS patients exhibit an intermediate autoimmune phenotype and demonstrated a genetic association between rare RNASEH2 sequence variants and SLE. Evaluation of patient cells revealed that SLE-and AGS-associated mutations impair RNase H2 function and result in accumulation of ribonucleotides in genomic DNA. The ensuing chronic low level of DNA damage triggered a DNA damage response characterized by constitutive p53 phosphorylation and senescence. Patient fibroblasts exhibited constitutive upregulation of IFN-stimulated genes and an enhanced type I IFN response to the immunostimulatory nucleic acid polyinosinic:polycytidylic acid and UV light irradiation, linking RNase H2 deficiency to potentiation of innate immune signaling. Moreover, UV-induced cyclobutane pyrimidine dimer formation was markedly enhanced in ribonucleotide-containing DNA, providing a mechanism for photosensitivity in RNase H2-associated SLE. Collectively, our findings implicate RNase H2 in the pathogenesis of SLE and suggest a role of DNA damage-associated pathways in the initiation of autoimmunity.

show abstract

Section: Carriers Of Ags Mutations Frequently Develop Sle-associated mentioning

confidence: 99%

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Günther¹,

Kind²,

Reijns³

et al. 2014

J. Clin. Invest.

196

178

View full text Add to dashboard Cite

show abstract

“…It is conceivable that lack of repair in NTera2 cells resulting from the repair-shielding role of HMGB4 will block S-phase progression because the lesions impede DNA polymerases (37). To investigate this possibility, we treated NTera2 and NTera2 HMGB4 −/− cells with cisplatin (2 μM) and used flow cytometry to assay cell cycle progression using ModFit.…”

Section: Hmgb4mentioning

confidence: 99%

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Awuah

Riddell

Lippard

2017

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cisplatin is the most commonly used anticancer drug for the treatment of testicular germ cell tumors (TGCTs). The hypersensitivity of TGCTs to cisplatin is a subject of widespread interest. Here, we show that high-mobility group box protein 4 (HMGB4), a protein preferentially expressed in testes, uniquely blocks excision repair of cisplatin-DNA adducts, 1,2-intrastrand cross-links, to potentiate the sensitivity of TGCTs to cisplatin therapy. We used CRISPR/ Cas9-mediated gene editing to knockout the HMGB4 gene in a testicular human embryonic carcinoma and examined cellular responses. We find that loss of HMGB4 elicits resistance to cisplatin as evidenced by cell proliferation and apoptosis assays. We demonstrate that HMGB4 specifically inhibits repair of the major cisplatin-DNA adducts in TGCT cells by using the human TGCT excision repair system. Our findings also reveal characteristic HMGB4-dependent differences in cell cycle progression following cisplatin treatment. Collectively, these data provide convincing evidence that HMGB4 plays a major role in sensitizing TGCTs to cisplatin, consistent with shielding of platinum-DNA adducts from excision repair.platinum anticancer drug | testicular cancer | high-mobility group protein T esticular germ cell tumors (TGCTs) are among the few tumor types that can be clinically cured with chemotherapy owing to the potency of cisplatin (1). The introduction of cisplatin in combination chemotherapy helped advance cure rates from 5% to the current level of 90% (2). In the clinic, cisplatin is used with bleomycin and either vinblastine or etoposide to treat metastatic testicular neoplasms (3-6). The well-studied antitumor activity of cisplatin involves binding to DNA, inhibition of transcription, and induction of apoptosis (7,8). Cellular events leading to apoptosis are multifactorial and begin with uptake followed by chemical transformation of cisplatin. Following aquation, or replacement of the chloride ligands in [Pt(NH 3 ) 2 Cl 2 ] by water, the activated drug binds to DNA, generating mainly 1,2-intrastrand d(GpG) cross-links that block RNA polymerase II, ultimately signaling cell death (9-11). Recently, a cisplatinsequencing (cisplatin-seq) approach was used to confirm DNA as the target for cisplatin at the genome scale by base resolution analysis (12). High-mobility group proteins such as high-mobility group box protein 1 (HMGB1) recognize these specific cisplatin-DNA adducts and promote the toxicity of cisplatin to tumors by interfering with excision and other repair pathways (13,14).HMGB1 binds selectively to cisplatin 1,2-intrastrand d(GpG) and d(ApG) cross-links, which account for ∼90% of all platinum (Pt)-DNA adducts (15,16). Studies of the interaction of HMGB1 and other cisplatin-DNA recognition proteins such as Irx1 in yeast (17, 18) with cisplatin-modified DNA revealed bending of the DNA with attendant shielding from excision repair in vitro and subsequent sensitization of cancer cells to cisplatin treatment (13,19). Related studies showed cooperative HMGB1 and XP...

show abstract

“…This nature of this response differs depending of the phase of the cell cycle. Although it has been established that UV lesions trigger a cell cycle arrest during replication in the S phase, the discovery and characterization of UV-induced damaged response in G 0 / G 1 cells is more recent (Novarina et al 2011). Because only this latter response is connected to NER, it will be the exclusive subject of our discussion.…”

Section: The Role Of Ner In Uv-induced Dna Damage Signalingmentioning

confidence: 99%

“…It is well known that a principal signal for activation of the DNA-damage response is a long stretch of ssDNA covered with RPA. Such filaments bind the ATR-ATRIP complex activating the ATR kinase activity and triggering downstream signals (Zou and Elledge 2003;Novarina et al 2011). Although an RPAcovered stretch of ssDNA is formed during NER following the incision reaction, this intermediate is short-lived and the ssDNA stretch not long enough to activate full ATR signaling.…”

Section: The Role Of Ner In Uv-induced Dna Damage Signalingmentioning

confidence: 99%

Nucleotide Excision Repair in Eukaryotes

2014

DNA Repair and Mutagenesis

View full text Add to dashboard Cite

Nucleotide excision repair (NER) is the main pathway used by mammals to remove bulky DNA lesions such as those formed by UV light, environmental mutagens, and some cancer chemotherapeutic adducts from DNA. Deficiencies in NER are associated with the extremely skin cancer-prone inherited disorder xeroderma pigmentosum. Although the core NER reaction and the factors that execute it have been known for some years, recent studies have led to a much more detailed understanding of the NER mechanism, how NER operates in the context of chromatin, and how it is connected to other cellular processes such as DNA damage signaling and transcription. This review emphasizes biochemical, structural, cell biological, and genetic studies since 2005 that have shed light on many aspects of the NER pathway. N ucleotide excision repair (NER) is the main pathway responsible for the removal of bulky DNA lesions induced by UV irradiation, environmental mutagens, and certain chemotherapeutic agents. The history of the discovery of NER, its association with genetic disorders, mechanistic features, and relationship with other cellular pathways has been extensively reviewed in 2005 in several articles in DNA Repair and Mutagenesis (Friedberg et al. 2005). Here, I will briefly reiterate how the field of NER developed over the past 50 years and then focus on how our knowledge has progressed since 2005.

show abstract

Mind the gap: Keeping UV lesions in check

Cited by 38 publications

References 103 publications

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Defective removal of ribonucleotides from DNA promotes systemic autoimmunity

Repair shielding of platinum-DNA lesions in testicular germ cell tumors by high-mobility group box protein 4 imparts cisplatin hypersensitivity

Nucleotide Excision Repair in Eukaryotes

Contact Info

Product

Resources

About