DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP

Mimmler, Maximilian; Schmidt, Péter; Kraus, A.; Stroh, Svenja; Nikolova, Teodora; Seiwert, Nina; Hasselwander, Solveig; Neitzel, Carina; Haub, Jessica; Monien, Bernhard H.; Nicken, Petra; Steinberg, Pablo; Shay, Jerry W.; Kaina, Bernd; Fahrer, Jörg

doi:10.1093/nar/gkw791

Cited by 31 publications

(34 citation statements)

References 62 publications

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“…To this end, 1 × 10 3 cells per milliliter were mixed with 5% low melting point agarose, transferred onto agarose-coated slides, and allowed to settle. The alkaline Comet assay was then performed as reported (49,50). In each experiment, at least 50 cells were scored per sample using the software Comet Assay IV (Perceptive Instruments).…”

Section: Methodsmentioning

confidence: 99%

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PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

Dörsam

Seiwert

Foersch

et al. 2018

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

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Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP-1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP-1 deficient (PARP-1) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1 mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up-regulation. PARP-1 animals were then crossed with -methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1/MGMT double knockout (DKO) mice developed more, but much smaller tumors than MGMT animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar -methylguanine levels. Studies with PARP-1 cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to -methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression.

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Section: Methodsmentioning

confidence: 99%

“…To inactivate cellular MGMT, cells were incubated with the potent MGMT inhibitor O 6 -benzylguanine (20 μM; Sigma Deisenhofen) for 2 h before TMZ addition. Cells were then harvested and processed for the alkaline Comet assay as described (49,50).…”

Section: Methodsmentioning

confidence: 99%

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

Dörsam

Seiwert

Foersch

et al. 2018

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

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“…PhIP is one of the most abundant heterocyclic amines formed during cooking meat at high temperatures . PhIP forms bulky DNA adducts at the C8‐position of guanine (C8‐PhIP‐dG) following metabolic activation . Formation of DNA adducts by alcohol derived reactive acetaldehydes and C8‐PhIP‐dG adducts in proliferating cells can interfere with the DNA replication machinery by blocking replicative polymerases .…”

Section: Consequences Of Genomic Instability At Fra16dmentioning

confidence: 99%

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

Hussain

Liu

Shrock

et al. 2018

Genes Chromosomes & Cancer

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WWOX is one of the largest human genes spanning over 1.11 Mbp in length at chr16q23.1‐q23.2 and containing FRA16D, the second most common chromosomal fragile site. FRA16D is a hot spot of genomic instability, prone to breakage and for causing germline and somatic copy number variations (CNVs). Consequentially WWOX is frequent target for deletions in cancer. Esophageal, stomach, colon, bladder, ovarian, and uterine cancers are those most commonly affected by WWOX deep focal deletions. WWOX deletions significantly correlate with various clinicopathological features in esophageal carcinoma. WWOX is also a common target for translocations in multiple myeloma. By mapping R‐loop (RNA:DNA hybrid) forming sequences (RFLS) we observe this to be a consistent feature aligning with germline and somatic CNV break points at the edges and core of FRA16D spanning from introns 5 to 8 of WWOX. Germline CNV polymorphisms affecting WWOX are extremely common in humans across different ethnic groups. Importantly, structural variants datasets allowed us to identify a specific hot spot for germline duplications and deletions within intron 5 of WWOX coinciding with the 5′ edge of the FRA16D core and various RFLS. Recently, multiple pathogenic CNVs spanning WWOX have been identified associated with neurological conditions such as autism spectrum disorder, infantile epileptic encephalopathies, and other developmental anomalies. Loss of WWOX function has recently been associated with DNA damage repair abnormalities, increased genomic instability, and resistance to chemoradiotherapy. The described observations place WWOX both as a target of and a contributor to genomic instability. Both of these aspects will be discussed in this review.

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“… 11 , 12 , 13 Furthermore, DSBs can arise indirectly due to the collapse of stalled replication forks at sites of DNA damage, for example bulky DNA adducts. 14 DSBs can result in chromosomal aberrations, which are causally linked to cancer formation, 15 and are a potent trigger of apoptotic cell death. 16 …”

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confidence: 99%

AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells

et al. 2017

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DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling.

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DNA damage response curtails detrimental replication stress and chromosomal instability induced by the dietary carcinogen PhIP

Cited by 31 publications

References 62 publications

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

PARP-1 protects against colorectal tumor induction, but promotes inflammation-driven colorectal tumor progression

WWOX, the FRA16D gene: A target of and a contributor to genomic instability

AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells

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