ATR Promotes Faithful Chromosome Segregation in Mitosis

Published OnlineFirst December 1, 2017; DOI: 10.1158/2159-8290.CD-RW2017-227

REsEARCh wATCh

Mitosis

Major finding: ATR localized to centro- Mechanism: ATR engages centromeric R Impact: ATR may be a therapeutic target meres to prevent lagging chromosomes loops in mitosis to activate Aurora B via in cancer cells vulnerable to chromo- independent of its role in replication stress . CHK1 to prevent lagging chromosomes . somal instability and replication stress .

Atr ProMotEs fAithfuL chroMosoME sEgrEgAtion in Mitosis The ATR kinase is an essential component of RPA, which serves as a sensor for ssDNA in R the response to DNA damage and replication loops. RPA-coated R loops generated by RNA poly- stress, and loss of ATR during DNA replication merase II–mediated transcription during mitosis increases genomic instability in S phase. Thus, were detected at centromeres in mitotic cells and ATR is a master regulator of genome integrity. promoted ATR activation. R-loop stabilization Unexpectedly, Kabeche and colleagues found that facilitated ATR-mediated Aurora B activation and ATR localized to centromeres on mitotic chro- faithful chromosome segregation. Collectively, mosomes, suggesting a potential role for ATR these fi ndings reveal a role for ATR in promoting in chromosome segregation. Inhibition of ATR increased faithful chromosome segregation in mitosis to maintain the rate of lagging chromosomes in anaphase, indicating genomic stability that is independent of its S-phase role in a role for ATR in promoting accurate whole-chromosome the DNA damage response. Further, these results suggest segregation separate from its S-phase functions. Mechanis- that ATR may be an effective therapeutic target in cancer tically, ATR phosphorylated CHK1 at centromeres, which cells that are vulnerable to defects in both chromosomal subsequently activated Aurora B to facilitate correction of instability and replication stress. n erroneous microtubule attachments at kinetochores. ATR localization to the mitotic centromeres was dependent on Kabeche L, Nguyen HD, Buisson R, Zou L. A mitosis-speciﬁ c and R Aurora A, CENP-F, and R loops (DNA–RNA hybrids with a loop–driven ATR pathway promotes faithful chromosome segregation. displaced single-stranded DNA), and ATR colocalized with Science 2017 Nov 23 [Epub ahead of print].

DnA Repair

Major finding: DNA mismatch repair in Concept: Loss of DNA mismatch repair Impact: Inhibition of DNA repair pro- tumors promotes enhanced immune drives hypermutation to increase the cesses is a potential adjuvant approach surveillance . tumor neoantigen repertoire . for immunotherapy .

Loss of dnA rEPAir drivEs nEoAntigEn rEnEWAL And inhibits tuMor groWth Mutations in genes associated with DNA mismatch in immune-competent mice. Consistent with these find- repair (MMR), such as MLH1, result in a microsatellite ings, MMR-deficient cells formed tumors in immune- instability (MSI) phenotype and promote tumor initia- competent mice depleted of CD8+ T cells. Longitudinal tion and growth; however, MMR-deficient cancers are exome sequencing revealed that mutational load, the associated with favorable prognosis. It has recently been number of neoantigens, and T-cell receptor diversity shown that immune checkpoint blockade is more effica- increased over time in MMR-deficient, but not MMR- cious in patients with MSI tumors than in patients with proficient, cells. Further, treatment with the genotoxic microsatellite stable (MSS) tumors. To elucidate the role agent temozolomide inactivated MMR in MMR-profi- of MMR in tumorigenesis and immunotherapy response, cient cancer cells, resulting in increases in mutational Germano and colleagues performed CRISPR/Cas9-mediated load and neoantigens and enhanced tumor immune sur- targeting of Mlh1 in murine breast, colon cancer, and pan- veillance in vivo. Similarly, decreased expression of the creatic ductal adenocarcinoma cells to generate isogenic DNA repair enzyme MGMT in human cancer cells and sets of MMR-proficient and MMR-deficient cell lines. tumors treated with temozolomide was associated with While both MMR-proficient and MMR-deficient cells alterations in MMR genes and high tumor mutation grew at similar rates and rapidly formed tumors in immu- burden and number of neoantigens. These findings show nocompromised mice, only MMR-proficient cells formed that MMR deficiency induces neoantigen production to subcutaneous and orthotopic tumors in immune-compe- promote durable immune surveillance and suggest that tent syngeneic mice; however, transplantation of MMR- inactivation of DNA repair may enhance the immuno- deficient tumors grown in immunocompromised mice genicity of MSS tumors. n to immune-competent mice resulted in tumor growth. Treatment with combined anti–PD-1 and anti-CTLA4 Germano G, Lamba S, Rospo G, Barault L, Magrì A, Maione F, antibodies resulted in decreased growth of transplanted et al. Inactivation of DNA repair triggers neoantigen generation and MMR-deficient tumors, but not MMR-proficient tumors, impairs tumour growth. Nature 2017;552:116–20.

January 2018 CANCER DISCOVERY | 11

ATR Promotes Faithful Chromosome Segregation in Mitosis

Cancer Discov 2018;8:11. Published OnlineFirst December 1, 2017.

Updated version Access the most recent version of this article at: doi:10.1158/2159-8290.CD-RW2017-227

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