Multifaceted activities of DNA polymerase η: beyond translesion DNA synthesis

Acharya, Narottam; Manohar, Kodavati; Peroumal, Doureradjou; Khandagale, Prashant; Patel, Shraddheya Kumar; Sahu, Satya Ranjan; Kumari, Premlata

doi:10.1007/s00294-018-0918-5

Cited by 32 publications

(21 citation statements)

References 66 publications

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“…A high prevalence of Signature 9 (POLN) was seen in at least one sample in seven of eight patients. This signature is associated with somatic hypermutation by polymerase h, a DNA polymerase that plays a role in DNA repair by translesion synthesis (22).…”

Section: Resultsmentioning

confidence: 99%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

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Section: Resultsmentioning

confidence: 99%

Evolutionary Origins of Recurrent Pancreatic Cancer

Sakamoto

Attiyeh

Gerold

et al. 2019

Preprint

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“…The TLS process has garnered considerable attention due to the tolerance of damage in DNA in an errorfree or error-prone manner (39,40). TLS also plays an important role in tolerance of ribonucleotides in DNA, and the main key player is hpol η (especially in dealing with lagging strands derived from Okazaki fragments) (16,24,38,(41)(42)(43)(44)(45)(46). Studies with 8-oxo-rG in DNA indicate that hpol η is required for the tolerance of this adduct (24).…”

Section: Introductionmentioning

confidence: 99%

Impact of 1,N6-ethenoadenosine, a damaged ribonucleotide in DNA, on translesion synthesis and repair

Ghodke

Guengerich

2020

Journal of Biological Chemistry

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Incorporation of ribonucleotides into DNA can severely diminish genome integrity. However, how ribonucleotides instigate DNA damage is poorly understood. In DNA, they can promote replication stress and genomic instability and have been implicated in several diseases. We report here the impact of the ribonucleotide rATP and of its naturally occurring damaged analog 1,N6-ethenoadenosine (1,N6-ϵrA) on translesion synthesis (TLS), mediated by human DNA polymerase η (hpol η), and on RNase H2–mediated incision. Mass spectral analysis revealed that 1,N6-ϵrA in DNA generates extensive frameshifts during TLS, which can lead to genomic instability. Moreover, steady-state kinetic analysis of the TLS process indicated that deoxypurines (i.e. dATP and dGTP) are inserted predominantly opposite 1,N6-ϵrA. We also show that hpol η acts as a reverse transcriptase in the presence of damaged ribonucleotide 1,N6-ϵrA but has poor RNA primer extension activities. Steady-state kinetic analysis of reverse transcription and RNA primer extension showed that hpol η favors the addition of dATP and dGTP opposite 1,N6-ϵrA. We also found that RNase H2 recognizes 1,N6-ϵrA but has limited incision activity across from this lesion, which can lead to the persistence of this detrimental DNA adduct. We conclude that the damaged and unrepaired ribonucleotide 1,N6-ϵrA in DNA exhibits mutagenic potential and can also alter the reading frame in an mRNA transcript because 1,N6-ϵrA is incompletely incised by RNase H2.

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“…Eukaryotic DNA replication requires the concerted action of several enzymes and accessory cofactors [1][2][3]. While helicases and DNA polymerases are the key enzyme components; replication factor C (RFC), proliferating cell nuclear antigen (PCNA) and replication protein A (RPA) are the integral structural components of the DNA replication machinery.…”

Section: Introductionmentioning

confidence: 99%

Identification of PCNA interacting protein motifs in human DNA polymerase delta

Khandagale

Thakur

Acharya

2020

Preprint

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AbstractDNA polymerase delta (Polδ) is a highly processive essential replicative DNA polymerase. In humans, Polδ holoenzyme consists of p125, p50, p68, and p12 subunits and recently, we have shown that p12 exists as a dimer. Extensive biochemical studies suggest that all the subunits of Polδ interact with the processivity factor proliferating cell nuclear antigen (PCNA) to carry out a pivotal role in genomic DNA replication. While PCNA interaction protein (PIP) motifs in p68, p50 and p12 have been mapped, the PIP in p125, the catalytic subunit of the holoenzyme, remains elusive. Therefore, in this study by using multiple approaches we have conclusively mapped a non-canonical PIP box from residues 999VGGLLAFA1008 in p125, which binds to inter domain-connecting loop of PCNA with high affinity. Collectively, including previous studies, we conclude that similar to S. cerevisiae Polδ, each of the human Polδ subunits possess motif to interact with PCNA and significantly contribute towards the processive nature of this replicative DNA polymerase.

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Multifaceted activities of DNA polymerase η: beyond translesion DNA synthesis

Cited by 32 publications

References 66 publications

Evolutionary Origins of Recurrent Pancreatic Cancer

Evolutionary Origins of Recurrent Pancreatic Cancer

Impact of 1,N6-ethenoadenosine, a damaged ribonucleotide in DNA, on translesion synthesis and repair

Identification of PCNA interacting protein motifs in human DNA polymerase delta

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