DNA replication is a vital process in all living organisms. At each cell division, > 30,000 replication origins are activated in a coordinated manner to ensure the duplication of > 6 billion base pairs of the human genome. During differentiation and development, this program must adapt to changes in chromatin organization and gene transcription: its deregulation can challenge genome stability, which is a leading cause of many diseases including cancers and neurological disorders. Over the past decade, great progress has been made to better understand the mechanisms of DNA replication regulation and how its deregulation challenges genome integrity and leads to human disease. Growing evidence shows that gene transcription has an essential role in shaping the landscape of genome replication, while it is also a major source of endogenous replication stress inducing genome instability. In this review, we discuss the current knowledge on the various mechanisms by which gene transcription can impact on DNA replication, leading to genome instability and human disease.
Autosomal recessive primary microcephaly, also known as MCPH, is a rare genetic condition where infants are born with small heads and brains. The causes of MCPH are often unknown or unclear. To date, 25 genes have been found to be associated with MCPH. Most of these genes serve similar roles in maintaining genome stability, being associated with centrosome and spindle function, chromosome dynamics, cell cycle regulation, cell division, brain development, neurogenesis, and/or the DNA damage response. In this review, we classify MCPH-associated genes based on their known functions, and propose potential novel functions of MCPH genes in DNA replication and/or the DNA replication stress response, and tumorigenesis. This classification provides a novel perspective on the underlying causes of MCPH and a comprehensive reference for future research.
The tumor suppressor p53 is activated in response to cellular stresses. The transcription factor p53 can activate the expression of numerous genes leading to cell cycle arrest, senescence or apoptosis. The p53 network exhibits complex stimulus-dependent dynamics under stressed and non-stressed conditions. Mathematical models contribute significantly to enhanced understanding of p53 network topology. In this review, we discuss the evolution of kinetic p53 modeling, multiple mechanisms for distinct p53 dynamics, and how the temporal p53 dynamics determine cell fate over the last 2 decades. The Information encoding and decoding strategies through p53 signaling network enable cells to undergo appropriate cellular outcomes.
Multiple myeloma (MM) is a malignant plasma cell proliferating in the bone marrow. Oncogenesis of MM is a multi-stage cytogenetic event. Among these, aberrant activation of the non-canonical nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway is critical for the oncogenic progression of MM. Tumor necrosis factor receptor‐associated factor 3 (TRAF3) mutation is among the most common tumor suppressor mutations in MM that allows constitutive activation of the non-canonical NF-кB pathway, thereby enhancing de novo survival of MM cells. Although there are some promising developments on current therapeutic regimens for MM patients that target such NF-кB signature, drug resistance perhaps remains a major concern. So far, TRAF3 mutation has been reported to modulate proteasome inhibitor response of MM. Mechanistically, concomitant to TRAF3 mutation-associated NIK stability that leads to the pathway activation, it has been reported that bortezomib treatment also causes a drastic increase in the level of NIK that causes pathway cross talk activating the canonical pathway, thereby triggering an acquired proteasome inhibitor resistance (PIR) pathway. Concomitantly targeting such NIK-driven acquired PIR or else targeting NIK than TRAF3 mutation and associated phenotype is likely to be the better option and thus remains to be elucidated. Hence, this review explains the roles of TRAF3-mutation-associated NF-кB pathway activation in the oncogenic progression and drug response of MM.
Chromosomal rearrangement involving 14q32 region that results in TNF receptor associated factor 3 (TRAF3) dysfunctional mutation is the most frequent NF-κB pathway mutation in multiple myeloma (MM). Subsequent NF-κB inducing Kinase (NIK) stabilization plays a critical role in alternative NF-κB activation. However, disease progression resulting from TRAF3 dysregulation has not been well understood. In this study, we identified lymphocyte cellular protein 1 (LCP1) as a novel NIK-driven alternative NF-κB target in TRAF3 dysfunctional mutation using RNA-seq, ChIP-seq (RelA/p65 and p52 NF-κB) and other validation methods. LCP1 is exclusively activated in MM cells with TRAF3 loss-of-function mutation. In MM patients, higher LCP1 expression was significantly pronounced in poor prognosis groups such as 4p16 and MAF. CD138 negative MM patient cells showed elevated LCP1 expression and inhibition of LCP1 can sensitize proteasome inhibitor bortezomib in TRAF3 mutant MM cells in vitro. We report that LCP1 is a NIK-driven biomarker in TRAF3 dysfunctional MM and targeting LCP1 can provide a valuable therapeutic intervention in TRAF3 mutated MM.