Ribonucleotide Reductase Small Subunit p53R2 Facilitates p21 Induction of G1 Arrest under UV Irradiation

Abstract

p53R2, which is one of the two known ribonucleotide reductase small subunits (the other being M2), is suggested to play an important role in supplying deoxynucleotide triphosphates (dNTP) for DNA repair during the G 1 or G 2 phase of the cell cycle. The ability of p53R2 to supply dNTPs for repairing DNA damages requires the presence of a functional p53 tumor suppressor. Here, we report in vivo physical interaction and colocalization of p53R2 and p21 before DNA damage. Mammalian two-hybrid assay further indicates that the amino acids 1 to 113 of p53R2 are critical for interacting with the NH 2 -terminal region (amino acids 1-93) of p21. The binding between p21 and p53R2 decreases inside the nucleus in response to UV, the time point of which corresponds to the increased binding of p21 with cyclindependent kinase-2 (Cdk2), and the decreased Cdk2 activity in the nucleus at G 1 . Interestingly, p53R2 dissociates from p21 but facilitates the accumulation of p21 in the nucleus in response to UV. On the other hand, the ribonucleotide reductase activity increases at the corresponding time in response to UV. These data suggest a new function of p53R2 of cooperating with p21 during DNA repair at G 1 arrest.

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“…132 In response to UV, however, this binding decreased resulting not only in an increase of the ribonucleotide reductase activity of p53R2, but also in an increased binding of p21 to CDK2 and a subsequent arrest of the cells in G1. Whether this entails an active shuttling process or a signaling event leading to nuclear stabilization of p21 was, however, not elucidated.…”

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“…[15][16][17] So there are two independent pathways in providing dNTPs: first, R2 provides dNTPs in S-phase and second, P53R2 provides dNTPs for DNA repair in G1 or G2-phase. 12 The maximum level of P53R2 has been found at G1/S transition. 6 Furthermore, P53R2 up-regulates P21 and down-regulates cyclin D, 15 causing cell cycle arrest in G1 and providing both time and dNTP for the repair of damaged DNA.…”

“…Subsequently, P53R2 accumulates in cell nuclear and increases RR activity. 12,13 However, P53R2 activation may not be fast enough to provide dNTPs immidiatly, which can be completed during a few hours after DNA damage. It is shown that ATM phosphorylates P53R2 in response to genotoxic stress.…”

“…6,15 In early G1-phase, R2, but not P53R2, is degraded by cadherin 1/anaphase promoting complex (Cdh1/APC). 12 Thus, in G1phase, P53R2 acts with R1 instead of R2 to provide dNTPs for DNA. [15][16][17] So there are two independent pathways in providing dNTPs: first, R2 provides dNTPs in S-phase and second, P53R2 provides dNTPs for DNA repair in G1 or G2-phase.…”

“…18,19 Moreover, P53R2 may plays a role in scavenging reactive oxygen species (ROS) and thereby protecting mitochondrial membrane from oxidative stress. 12 In addition, P53R2 down-regulates MEK-ERK signal pathway through direct interaction with ERK-Kinase2. 20 MEK-ERK signaling pathway regulates various cellular processes including cell cycle progression and cell survival, thus inhibition of this pathway is another anti-cancer property of P53R2.…”