PCNA, a focus on replication stress and the alternative lengthening of telomeres pathway

Shen, Michelle; Young, Adrian; Autexier, Chantal

doi:10.1016/j.dnarep.2021.103055

Cited by 13 publications

(10 citation statements)

References 153 publications

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“…HUS1 is part of the 911 (RAD9-RAD1-HUS1) checkpoint that activates ATR and protects telomere integrity during DNA damage response and oxidative stress [ 47 , 65 ]. SENP5 is a key protein in the SUMOylation pathway [ 54 , 66 ], UBE2I is a positive regulator of APBs [ 54 , 55 ], DNMT1 depletion is related to ALT activation [ 47 ] and ATM and PCNA have been observed to colocalize with APBs during HR and HDR [ 67 , 68 ]. Finally, to summarize the role of the 13 key APBs-related proteins, a heatmap was elaborated showing the 21 most significant pathways in which they are interacting ( Figure 7 ).…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway

Armendáriz‐Castillo

K²,

Pérez-Villa³

et al. 2022

Biology

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Alternative lengthening of telomeres-associated promyelocytic leukemia nuclear bodies (APBs) are a hallmark of telomere maintenance. In the last few years, APBs have been described as the main place where telomeric extension occurs in ALT-positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multiomics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 Pan-Cancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT-positive cancers in the future.

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Section: Discussionmentioning

confidence: 99%

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway

Armendáriz‐Castillo

K²,

Pérez-Villa³

et al. 2022

Biology

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show abstract

“…HUS1 is part of the 911 (RAD9-RAD1-HUS1) checkpoint which activates ATR and protects telomere integrity during DNA damage response and oxidative stress (41,52). SENP5 is a key protein in the SUMOylation pathway (42,53), UBE2I is a positive regulator of APBs (42,43), DNMT1 depletion is related to ALT activation (41) and ATM and PCNA have been observed to colocalize with APBs during HR and HDR (54,55). Finally, to summarize the role of the 13 key APBs-related proteins, a heatmap was elaborated showing the 21 most significant pathways in which they are interacting (Figure 6).…”

Section: Discussionmentioning

confidence: 99%

Identification of Key Proteins in the Alternative Lengthening of Telomeres Associated Promyelocytic Leukemia Nuclear Bodies

Armendáriz‐Castillo¹,

K²,

Pérez-Villa³

et al. 2021

Preprint

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One of the hallmarks of the Alternative Lengthening of Telomeres (ALT) is the association with Promyelocytic Leukemia (PML) Nuclear Bodies, known as APBs. In the last years, APBs have been described as the main place where telomeric extension occurs in ALT positive cancer cell lines. A different set of proteins have been associated with APBs function, however, the molecular mechanisms behind their assembly, colocalization, and clustering of telomeres, among others, remain unclear. To improve the understanding of APBs in the ALT pathway, we integrated multi-omics analyses to evaluate genomic, transcriptomic and proteomic alterations, and functional interactions of 71 APBs-related genes/proteins in 32 PanCancer Atlas studies from The Cancer Genome Atlas Consortium (TCGA). As a result, we identified 13 key proteins which showed distinctive mutations, interactions, and functional enrichment patterns across all the cancer types and proposed this set of proteins as candidates for future ex vivo and in vivo analyses that will validate these proteins to improve the understanding of the ALT pathway, fill the current research gap about APBs function and their role in ALT, and be considered as potential therapeutic targets for the diagnosis and treatment of ALT positive cancers in the future.

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“…PARP (Poly ADP-ribose polymerase), a key enzyme in the repair of DNA damage, is a superfamily of multi-domain proteins [ 30 ]. Each PARP protein has a highly conserved (ADP-ribosyltransferase) domain that can catalyze the transformation of nicotinamide lysed adenine dinucleotide (NAD+) into nicotinamide and ADP-ribose [ 31 ]. During BER, FEN1 was recruited to DNA damage sites by activated PARP1 [ 32 ].…”

Section: Overview Of Fen1mentioning

confidence: 99%

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

Yang

Guo

2022

Biomolecules

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DNA damage repair plays a key role in maintaining genomic stability and integrity. Flap endonuclease 1 (FEN1) is a core protein in the base excision repair (BER) pathway and participates in Okazaki fragment maturation during DNA replication. Several studies have implicated FEN1 in the regulation of other DNA repair pathways, including homologous recombination repair (HRR) and non-homologous end joining (NHEJ). Abnormal expression or mutation of FEN1 in cells can cause a series of pathological responses, leading to various diseases, including cancers. Moreover, overexpression of FEN1 contributes to drug resistance in several types of cancers. All this supports the hypothesis that FEN1 could be a therapeutic target for cancer treatment. Targeting FEN1 has been verified as an effective strategy in mono or combined treatment of cancer. Small-molecule compounds targeting FEN1 have also been developed and detected in cancer regression. In this review, we summarize the recent development of small-molecule inhibitors targeting FEN1 in recent years, thereby expanding their therapeutic potential and application.

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PCNA, a focus on replication stress and the alternative lengthening of telomeres pathway

Cited by 13 publications

References 153 publications

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway

Identification of Key Proteins in the Alternative Lengthening of Telomeres Associated Promyelocytic Leukemia Nuclear Bodies

Small-Molecule Inhibitors Targeting FEN1 for Cancer Therapy

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