is an absolute requirement for the downstream activities of the major base excision repair enzymes, it may act as a regulator for the base excision repair pathway for efficient and balanced repair of damaged bases, which are often less toxic and/or mutagenic than their subsequent repair product intermediates.Cellular DNA is continuously exposed to endogenous or exogenous chemical or physical agents that induce DNA lesions. DNA base damage threatens genomic stability and cellular viability. Multiple DNA repair pathways exist in all organisms, from bacteria to humans, to preserve the integrity of the genome (1). If not repaired, damaged bases could be mutagenic (2) and/or cause cell death by blocking DNA replication (3).In all organisms, repair of DNA-containing small adducts, as well as altered and abnormal bases, occurs primarily via the base excision repair (BER) 2 pathway, beginning with cleavage of the base by a DNA glycosylase (1, 2). Mechanistically, DNA glycosylases are categorized into two classes: mono-and bifunctional DNA glycosylases. Monofunctional DNA glycosylases, such as N-methylpurine-DNA glycosylase (MPG) and uracil-DNA glycosylase, use an activated water molecule as a nucleophile to generate an apurinic or apyrimidinic (AP) site in DNA. Bifunctional DNA glycosylases/AP lyases, such as NTH1 and OGG1, use an activated amino group (Lys) or imino group (Pro) as the nucleophile to create a Schiff base intermediate that coordinates base removal and subsequent strand incision (AP lyase) 3Ј to the AP site (4, 5). The mammalian MPG is known to excise at least 17 structurally diverse modified bases from DNA (6). These lesions include 3-alkylpurines, 7-alkylguanine, 1,N 6 -ethenoadenine (⑀A), N 2 ,3-ethenoguanine, and hypoxanthine (Hx), all of which are purine derivatives (7-12). Moreover, the base alterations are located in both the major and minor grooves of duplex DNA. Its orthologs in Escherichia coli (AlkA) and yeast (MAG) have an overlapping although not identical substrate range. Nonetheless mammalian MPG and E. coli AlkA do not share significant sequence similarity or structural homology (13,14), despite this functional similarity and the fact that 3-methyladenine is a preferred substrate for both. MPG excises ⑀A and Hx more efficiently than AlkA and MAG (11), but unlike AlkA, it cannot excise O 2 -alkylpyrimidines (15, 16) and oxidized bases such as 5-formyluracil and 5-hydroxymethyluracil (17) (22); however, the reduction was more pronounced for the AP-lyase activity. The Schiff base formation between hOGG1-and 8-oxoG-containing DNA was abrogated in the presence of Mg 2ϩ . These results suggest that hOGG1 operates mainly as a monofunctional glycosylase under physiologic concentrations of Mg 2ϩ (22). There

SUMMARY Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and the Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing ROS that on one hand induces NFkB signaling and expression of inflammatory cytokines, and on the other activates p53 checkpoint and senescence programs dampening the cyclinD1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.

Epithelioid sarcoma, in the relapse-refractory setting, has limited expected survival. SMARCB1 inactivation, common in epithelioid sarcoma, causes loss of INI1 protein expression and overexpression of the cancer cell growth promoting methyltransferase enzyme, EZH2. We treated a 19-year-old male with stage IV SMARCB1 inactivated epithelioid sarcoma presenting with recurrent end stage (Eastern Cooperative Oncology Group Performance Status 4) rapidly progressing bulky disease with combination ipilimumab and nivolumab. He failed standard therapy and an EZH2 inhibitor (tazemetostat). He presented (May 13, 2019) with a large (16.1×18.6 cm) soft tissue back mass extending from T10 to L3. Complete clinical regression of the back mass occurred within 2 weeks (May 28, 2019) of cycle 1 of combined checkpoint inhibition therapy followed by a positron emission tomography–negative complete remission (October 11, 2019). After a second negative positron emission tomography/computed tomography scan (January 13, 2020), checkpoint inhibition therapy was discontinued. He has returned to normal activities with a normal physical examination and Eastern Cooperative Oncology Group Performance Status of 0 at his last visit (June 29, 2020). In conclusion, combined checkpoint inhibition therapy warrants further study in the salvage setting in patients with epithelioid and other INI1 protein–deficient sarcomas seemingly regardless of prior therapy, extent of disease, and performance status.