Δ133p53/FLp53 predicts poor clinical outcome in esophageal squamous cell carcinoma

Tu, Qimin; Gong, Hongjian; Yuan, Chunhui; Liu, Gao; Huang, Jinqi; Li, Zhichao; Luo, Jianfei

doi:10.21203/rs.2.15278/v1

Cited by 1 publication

(1 citation statement)

References 33 publications

(49 reference statements)

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“…Accumulating evidence has shown that an increased ratio of ΔN-isoforms/p53α is associated with poorer overall survival or cancer aggressiveness, particularly for Δ133p53 in esophageal squamous cell carcinoma [62], Cholangiocarcinoma [63], and prostate cancer [64]. Here, we showed, that alternative p53isoforms, Δ133p53α and Δ160p53α, in particular, interfere with coexpressed p53α in DDT.…”

Section: Alternative P53-isoforms Show Loss-of-function In the P53-polι-dependent Ddt-pathway Mediating Homology-directed Bypass Of Replimentioning

confidence: 48%

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

et al. 2021

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The recently discovered p53-dependent DNA damage tolerance (DDT) pathway relies on its biochemical activities in DNA-binding, oligomerization, as well as complex formation with the translesion synthesis (TLS) polymerase iota (POLι). These p53-POLι complexes slow down nascent DNA synthesis for safe, homology-directed bypass of DNA replication barriers. In this study, we demonstrate that the alternative p53-isoforms p53β, p53γ, Δ40p53α, Δ133p53α, and Δ160p53α differentially affect this p53-POLι-dependent DDT pathway originally described for canonical p53α. We show that the C-terminal isoforms p53β and p53γ, comprising a truncated oligomerization domain (OD), bind PCNA. Conversely, N-terminally truncated isoforms have a reduced capacity to engage in this interaction. Regardless of the specific loss of biochemical activities required for this DDT pathway, all alternative isoforms were impaired in promoting POLι recruitment to PCNA in the chromatin and in decelerating DNA replication under conditions of enforced replication stress after Mitomycin C (MMC) treatment. Consistent with this, all alternative p53-isoforms no longer stimulated recombination, i.e., bypass of endogenous replication barriers. Different from the other isoforms, Δ133p53α and Δ160p53α caused a severe DNA replication problem, namely fork stalling even in untreated cells. Co-expression of each alternative p53-isoform together with p53α exacerbated the DDT pathway defects, unveiling impaired POLι recruitment and replication deceleration already under unperturbed conditions. Such an inhibitory effect on p53α was particularly pronounced in cells co-expressing Δ133p53α or Δ160p53α. Notably, this effect became evident after the expression of the isoforms in tumor cells, as well as after the knockdown of endogenous isoforms in human hematopoietic stem and progenitor cells. In summary, mimicking the situation found to be associated with many cancer types and stem cells, i.e., co-expression of alternative p53-isoforms with p53α, carved out interference with p53α functions in the p53-POLι-dependent DDT pathway.

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Section: Alternative P53-isoforms Show Loss-of-function In the P53-polι-dependent Ddt-pathway Mediating Homology-directed Bypass Of Replimentioning

confidence: 48%

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

et al. 2021

View full text Add to dashboard Cite

show abstract

Δ133p53/FLp53 predicts poor clinical outcome in esophageal squamous cell carcinoma

Cited by 1 publication

References 33 publications

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

p53 isoforms differentially impact on the POLι dependent DNA damage tolerance pathway

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